Juvenile idiopathic arthritis-associated uveitis in the era of biological therapy: how the disease changed in more than 20 years of observation in a tertiary referral center in Rome (Italy).

OBJECTIVES: To describe the ophthalmological characteristics in a Juvenile idiopathic arthritis (JIA) cohort and to evaluate how therapeutic advances have changed the course of the uveitis. METHODS: Analysis of a retrospective cohort study of consecutive JIA pediatric patients including JIA-associated uveitis (JIA-U) and comparison with a previous study in the same uveitis center assessed before the wide-spread of biological therapy. RESULTS: The total of 49 JIA patients were analyzed, of whom 18 JIA-U, compared with a JIA-U past cohort of 66 patients. Systemic corticosteroids were used significantly less in the current JIA-U group (p = 0.008) than in the past one. JIA-U present cohort was on therapy more frequently with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) than the past group (p = 0.039), mostly treated with methotrexate (93.3%). Furthermore, a larger use of biologic disease-modifying anti-rheumatic drugs (bDMARDs) was described in the current JIA-U group (p = 0.005) also associated with csDMARDs (p = 0.003). Adalimumab was used more (72.7%) in the present JIA-U cohort compared to a larger treatment with infliximab (61.5%) in the past (p = 0.005). Higher number of uveitis recurrences was observed in the previous cohort compared to the current one (p = 0.005). Fewer complications were described in this study than in the previous: posterior synechiae (p = 0.007), cataract (p < 0.001), band keratopathy (p < 0.001), and elevated intraocular pressure (IOP) (p = 0.047). CONCLUSION: Current therapies reduced the uveitis recurrences and ocular complications including cataract due also to the lower use of corticosteroids. The new close collaboration with the pediatric rheumatologic center in the same University has contributed to the care improvement and decrease of uveitis complications.

Pediatric urticaria in the Emergency Department: epidemiological characteristics and predictive factors for its persistence in children.

Summary: Introduction. Acute urticaria (AU) in children is a common clinical manifestation responsible for admission to the emergency department (ED). We aimed to analyze the epidemiological characteristics of AU in children and to identify predictors of both severity and progression. Material and methods. We evaluated 314 children admitted to the ED with a diagnosis of AU. We analyzed information concerning its onset, duration, severity, possible triggering factors, and the persistence of symptoms after 1, 3, and 6 months. Results. The most common etiological factors were infections (43.9%); in up to 32.4% of cases, AU was considered as idiopathic. AU was significantly most common in males and pre-school children. At the 6-month follow-up, 9.5% of children presented a persistence of urticaria, mainly those with contact (44.4%) or idiopathic (30.4%) forms. Conclusions. The AU etiology identified by history in the ED may be a significant predictor of persistence after a first attack of AU.

New methods and tools to assess nutritive sucking in new-borns: effect of different feeding bottles on nutritive performance.

Nutritive sucking is a fundamental process assuring the primary infant nourishment in the first months of life. When feeding is impaired for pathological conditions, the growth of the infant may be delayed with a cascade effect on the overall development. While literature studied nutritive sucking development in infants with feeding problems, like in severe premature babies or with low weight at birth, few works assesses to what extent different feeding bottles may influence feeding performance of healthy new-borns. This work proposes a method for functional characterization of feeding bottles based on the most promising and reliable indices used to quantitatively assess feeding skills in clinical applications. Thirty healthy newborns have been fed with two different bottles instrumented with a device for feeding monitoring. Their impact on feeding performance is objectively assessed and discussed. The approach presented here, even if preliminary, paves the way to a new method for functional characterization of feeding bottles. Further studies may allow to confirm our analyses with a higher number of bottles and infants.

Idiopathic intracranial hypertension in a paediatric population: a retrospective observational study on epidemiology, symptoms and treatment.

Idiopathic intracranial hypertension (IIH) is a disorder of unknown origin, which is characterized by elevated intracranial pressure (ICP) without underlying etiological evidence of neurological disease. The purpose of the current study was to evaluate epidemiological features, clinical presentation, diagnostic findings and treatment of sixteen children (7 males and 9 females) with IIH. Medical records of the patients were obtained from the University Paediatric Hospital of Catania, Italy. Clinical features, investigations and treatment approaches were retrieved. The mean age of the sixteen children at onset of symptoms was 9 years (range: 4 to 16 years). Most of the patients were classified as pre-pubertal. Mean BMI was 28.9 kg/m2. In 93.75% of patients headache was the presenting clinical symptom; and in the same percentage papilledema was detected as the accompanied sign during diagnostic flow-chart. The mean lumbar puncture opening pressure (LPOP) was 350 mm H2O. Fifty percent of the cases had normal brain imaging, while 12.5% showed enlarged optic nerve diameter and one patient had an intraocular protrusion of the optic nerve on MRI. Two patients (12.5%) had venous sinus stenosis, and one case showed an abnormal spinal MRI. With regard to therapeutic approaches, 93.75% of the cases were successfully treated with Acetazolamide. None of the patients required surgical procedures, and all neuroimaging findings disappeared after receiving treatment. In the present study we investigated the association of IIH with venous sinus stenosis. We also found ocular ultrasound to be a useful non-invasive alternative method for determining papilledema in paediatric IIH, specifically in an emergency.

Headache, migraine and obesity: an overview on plausible links.

Headache can represent different disorders with different etiologies; including cardiac, cerebral, vascular, psychiatric, metabolic, neurologic diseases. Recent studies have highlighted that obesity is significantly associated with headache and disability in adults. This rule also applies to children. This review focuses on literature data studying any eventual relationship between headache, migraine and obesity [shown in Body Mass Index (BMI)] in children. Research data have highlighted that there is a relationship between headache physiopathology and central and peripheral mechanisms responsible for food assumption. In this regard, neurotransmitters such as serotonin, and peptides such as orexin and adipocytokines (adiponectin and leptin) seem to play a key role both in food assumption and in headache pathogenesis. These data further emphasize the potential association between headache and BMI. Therefore, those therapeutic strategies aiming to decrease BMI may represent a model of useful treatment to understand whether weight loss reduces the incidence and the severity of headache in obese children. In conclusion, considering the effects of obesity and weight loss on the natural history of headache, important changes are expected in therapeutic management of paediatric headaches.

Congenital muscular dystrophy and epilepsy: a prospective case series of pediatric patients.

Congenital Muscular Dystrophies (CMDs) can be considered as a heterogeneous group of diseases characterized by marked weakness, generalized hypotonia and joint contractures. They are divided into pure and classical forms, without ocular and cerebral involvement, and complex forms, which are associated with cerebral abnormalities. Seizures have rarely been described in the pure forms while they seem to occur more frequently in complex forms. The aim of our study was to evaluate the incidence of seizure in CMD. Herein, the authors describe 16 cases of congenital muscular dystrophy (CMD) associated with different kinds of epileptic events, in order to study the pathogenic connection between the two clinical manifestations. In all described patients we reviewed the clinical, neurophysiologic, and neuroimaging data to determine any associations with epilepsy. The patients were divided into two groups: 14 cases with merosin positive CMD in one group and 2 patients with Walker Warburg syndrome (WWS) in the second group. In our study we found that in the first group, one benign myoclonic epilepsy (BME), one benign febrile convulsions had occurred. Also in one patient, the EEG revealed a moderately high voltage slow background with diffuse sharp waves reaching 300mV in amplitude with no clinical signs. In the merosin positive CMD patients, the presence of two different epileptic diseases, benign myoclonic epilepsy (BME) in one and febrile convulsion with tonic clinic seizures, may represent a new expression of merosine-positive congenital muscular disease (PCMD) in which the deficiency of an undiscovered muscular protein with a cerebral isoform may be the cause of epileptic events in this group of patients.

Efficacy and safety of omalizumab in paediatric age: an update of literature data.

Immunoglobulin E (IgE) was discovered in 1966 and was found responsible for immune defense against helminths, type I hypersensitivity and allergic diseases. IgE mediates allergic responses by binding to Fc receptors (the high affinity Fc-epsilon receptor I and the low affinity Fc-epsilon receptor II or CD23) expressed on tissue mast cells and blood basophils. This binding leads to degranulation and release of pro-inflammatory mediators. Considering the pivotal role of IgE in allergic diseases, antibodies against IgE potentiate an array of new therapeutic strategies and in this regard omalizumab (rhuMAb-E25, Xolair) has been developed as a monoclonal biologic drug to block serum IgEs. Although the use of omalizumab has been studied vigorously in many adult populations with allergic diseases, there are few heterogenous studies on children. There are very few ongoing clinical trials with omalizumab exclusively on children, although some adult studies have concluded pediatric patients as a part of their studies. Nevertheless, in pediatric clinical trials omalizumab has been demonstrated to be effective and safe also in this age group. Herein, the authors present a systematic review of extensive literature data on the use of omalizumab in children and adolescents.

Parasympathetic nervous system involvement in food allergy: description of a paediatric case.

The latest research data emphasize the interaction between the nervous and the immune systems. It has been demonstrated that the central nervous system (CNS) can be involved secondarily due to blood brain barrier (BBB) disruption via pro-inflammatory cytokines released in allergy. More recently it was demonstrated that the parasympathetic nervous system (PNS) could also be equally involved in models of peripheral inflammation such as food allergy; although this last clinical presentation has rarely been described. Herein, the authors report the case of a five-year-old Caucasian female who was admitted to our Pediatric Acute and Emergency Operative Unit for cyclic vomiting. Her vomiting, which was preceded by objective torque vertigo, headache and weakness, had been recurring with constant frequency every two months since she was 3 years old. After a complex diagnostic flow-chart, it was found that this spectrum of neurologic symptoms was due to a food allergy syndrome, which postulates some etiopathogenic hypotheses to explain the relationship between the two mentioned diseases.

Pregnancy in a methylmalonic acidemia patient with kidney transplantation: a case report.

Presently pregnancy is no more exceptional in women with metabolic diseases. However, it still poses significant medical problems both before and after childbirth. The challenge is even greater if the mother has undergone organ transplantation, because of her metabolic disease. We report on a case of pregnancy in a patient 29-year-old with methylmalonic acidemia cblA type (OMIM 251100) who received a renal transplantation at the age of 17 for end-stage renal disease (ESRD) caused by her primary disease. During pregnancy neither metabolic crises nor renal function changes were observed in the mother, with the only exception of a mild increase of her systemic blood pressure. To the fetus pregnancy was uneventful and during the first 30 months after birth the baby's neuropsychomotor development was normal and there were no episodes of metabolic derangement. This is evidence that methylmalonicacidemia cblA, even when treated with renal transplantation for inherent ESRD, is no contraindication to pregnancy. It is even possible that a functioning transplanted kidney contributes to improve metabolic parameters.

Vitamin E supplementation and oxidative status of peripheral blood mononuclear cells and lymphocyte subsets in hemodialysis patients.

Increased oxidative damage to cell membrane constituents causes profound changes in the membrane cytoarchitecture and modifications of the membrane physiological properties, e.g., the ability to respond to hormonal stimuli. In uremic patients receiving intermittent hemodialysis, a metabolic block of the phosphate pentose shunt has been described. This leads to insufficient detoxication of the hydroxyl radicals formed within the cells and therefore to increased oxidative damage to the polyunsaturated fatty acid constituents of the cell membranes. Vitamin E is known to reduce this oxidative damage and its harmful effects. We studied vitamin E (alpha-tocopherol acetate) administration in 10 chronically uremic patients receiving intermittent hemodialysis for positive effects on cell membrane-receptor response. The patients were studied before and after treatment for the extent of oxidative damage in peripheral mononuclear cells and for response to monoclonal antibodies to specific markers of T-lymphocyte subsets. After vitamin E treatment, oxidative damage decreased, and the membranes of peripheral mononuclear cells contained greater amounts of some unsaturated fatty acids. This is in agreement with a modification of the membrane phenotype markers of T-lymphocyte subsets and seems to confirm in vivo that changes in membrane structure first induced by increased oxidative damage due to the blockage of the phosphate pentose shunt can be reduced by the antioxidant action of vitamin E, which significantly influences the expression of membrane determinants.

Red blood cell lipid peroxidation in predialysis chronic renal failure.

In hemodialysis patients the pentose-phosphate shunt activity is deficient. As a consequence, the lipid peroxidation of the erythrocyte membranes is increased as shown by the increase in malonyldialdehyde concentrations and is accompanied by a decrease of the level of vitamin E in RBC. In the present study we have found that increased lipid peroxidation of the erythrocyte membranes is present also in chronic renal failure patients in the predialysis state, provided that the serum creatinine levels are higher than 5 mg/dl.

Vitamin E supplementation in hemodialysis patients: effects on peripheral blood mononuclear cells lipid peroxidation and immune response.

Lipid peroxidation and vitamin E levels in peripheral blood mononuclear cells (PBMC) were studied in 10 patients on maintenance hemodialysis. Significant increases of PBMC malonyldialdehyde (MDA) were detected, together with low vitamin E levels. After a fifteen-day-course of parenteral vitamin E supplementation, PBMC MDA reverted to normal values, while PBMC vitamin E levels remained lower than controls. In a parallel study an immunological monitoring was performed in the same patients before and after vitamin E supplementation. NK activity and PHA blastogenesis were not influenced by treatment, while a reduction of the number of OKT8+ lymphocytes were observed after vitamin E therapy. It is tempting to speculate that peroxidative damage of PBMC cell membranes in hemodialysis patients could, by impairing their functionality, influence immune responses and expression of functionally relevant membrane determinants.

Effects of alpha-tocopherol administration on red blood cell membrane lipid peroxidation in hemodialysis patients.

The result of vitamin E treatment in 19 uremic patients in chronic hemodialysis is evaluated. In particular, the levels of erythrocyte malonyldialdehyde (MDA) and vitamin E were determined, and the fatty acid composition of red blood cell (RBC) membrane before and after treatment with parenterally administered vitamin E. A decrease of RBC MDA levels, an increase of RBC vitamin E concentrations, and a decreased saturated fatty acid to unsaturated fatty acid ratio were found after treatment with vitamin E. There was a statistically significant increase of the packed RBC volume.

Red blood cell membrane lipid peroxidation and resistance to erythropoietin therapy in hemodialysis patients.

BACKGROUND: Chronic hemolysis, inadequate production of erythropoietin (EPO) or an impaired response of erythroid stem cells to EPO are the main factors of anemia in end-stage renal disease (ESRD) patients. Oxidative damage of red blood cell (RBC) membrane is a well-established cause of chronic hemolysis in hemodialysis (HD) patients. Administration of high-dose recombinant human EPO (rHuEPO) fails to correct anemia in 5 to 10% HD patients although all established factors of resistance to rHuEPO therapy have been previously ruled out or corrected. PATIENTS AND METHODS: We investigated the degree of RBC membrane oxidative damage in 9 HD patients who failed to respond to maximal rHuEPO administration (more than 200 UI/Kg weekly for 4 months consecutively, group A), compared to 10 patients who showed a good response to standard rHuEPO therapy (group B) and to 10 patients who needed no treatment (group C). RBC malondialdehyde (MDA) was assumed as the index of oxidative stress in erythrocyte membrane. RESULTS: No significant difference in erythrocyte MCV and MCHC, iron status, parathyroid function, aluminum and dialysis-related blood loss was observed between patients of group A, B and C. RBC MDA, reticulocyte count, plasma-free hemoglobin (fhb) and serum lactate dehydrogenase (LDH) were significantly higher while plasma haptoglobin was significantly lower in patients of group A compared to patients of groups B and C. Moreover, a significant inverse relationship was observed between RBC MDA and either plasma hemoglobin, RBC count and hematocrit when all patients were evaluated together. CONCLUSION: In conclusion, increased oxidative damage of RBC membrane is often detectable in HD patients who fail to respond to rHuEPO administration even in the absence of all established factors of resistance to EPO. Peripheral response to rHuEPO may be normal in these patients and persistent anemia may be related to enhanced hemolysis due to oxidative stress. Oxidative damage itself may therefore be considered a factor of resistance to EPO.

Administration of GSH has no influence on the RBC membrane: oxidative damage to patients on hemodialysis.

In patients on hemodialysis, a metabolic block of the pentose phosphate shunt has been described that impairs the reduction of oxidized glutathione. The block results in lack of detoxication of the free hydroxyl radicals produced inside the red blood cell (RBC) and causes oxidative damage to the polyunsaturated fatty acids of the RBC membrane that results in formation of aldehydes. Malonyldialdehyde has been used as an index of the oxidative damage. In a study group of 13 patients on hemodialysis, the authors have tested whether administering reduced glutathione (GSH) at 1200 mg/day for 1 month could minimize oxidative damage to the RBC membranes and improve the hematologic parameters. Treatment with GSH was followed by significant improvement of hematocrit (P = 0.008), hemoglobin (P = 0.03), and RBC count (P = 0.0037); however, oxidative damage to the membranes was increased (P = 0.0004), which suggests that improvement of the hematologic parameters is not related to reduction of the oxidative damage. This is because oxidized glutathione, formed in the oxidative process, cannot be reduced back to GSH because of alteration of the pentose phosphate shunt.

Oxidative damage to RBC membranes and pentose phosphate shunt activity in hemodialysis patients after suspension of erythropoietin treatment.

During follow-up of anemic hemodialysis patients (HDP) treated with recombinant human erythropoietin (rHuEpo), it was noticed that in five HDP, some time after suspension of rHuEpo, hemoglobin (Hb) levels remained at acceptable levels. A metabolic block of the pentose phosphate shunt (PPS) has been described in HDP, which leads to increased oxidative damage of red blood cell (RBC) membranes and increased susceptibility to hemolysis. The increased production of short-chain fatty aldehydes, including malonyldialdehyde (MDA), is an appropriate index of oxidative damage. This study aimed to verify whether the maintenance of acceptable levels of Hb was related to a change in RBC membrane oxidative damage and pentose phosphate shunt activity. In the five HDP in question who required rHuEpo (150 U/kg/week) for severe anemia (Hb = 7.48 +/- 0.95 g/dl), after a stable level of Hb > 10 g/dl was reached for at least 1 month, rHuEpo treatment was stopped. Hb levels remained adequate (Hb = 10.68 +/- 0.77 g/dl) after 14.6 +/- 7.64 months. The oxidative damage was evaluated by measuring RBC MDA (microgram/ml packed RBC) basal levels, and PPS activity by measuring MDA levels after incubation with ascorbate and cyanide (delta % RBC MDA production). Ten anemic HDP not treated with rHuEpo were used as controls (Hb = 8.12 +/- 1.32 g/dl). It was found that the maintenance of adequate levels of serum Hb after suspension of rHuEpo therapy is related to a decrease in RBC membrane oxidative damage (RBC MDA HDP = 2.40 +/- 0.41 vs. RBC MDA controls = 18.23 +/- 6.56; P < 0.005) in consequence of the normalization of pentose phosphate shunt activity.

Lack of oxidative damage in serum polyunsaturated fatty acids before and after dialysis in chronic uremic patients.

We described previously that in the erythrocytes and mononuclear blood cells from uremic patients on chronic hemodialysis, the membrane concentrations of malonyldialdehyde (MDA), resulting from peroxidation of polyunsaturated fatty acids (PUFA) in the membrane itself increased, and the concentrations of vitamin E (VIT E), the major antioxidizing agent, were lower. In the present study we analysed whether similar oxidative damage is seen in the serum from hemodialysis patients and whether the serum fatty acid pattern is affected. No evidence was found of oxidative damage in the serum during hemodialysis, serum concentrations of MDA and VIT E remaining constant before and after dialysis. No change was observed in serum pattern of PUFA, particularly linoleic acid. We therefore assume that the oxidative damage described in uremic patients is mainly intracellular.

[Reye's syndrome: pathogenetic problems (author's transl)]. / La sindrome di Reye: problemi patogenetici.

The authors describe six subjects with Reye's syndrome. All subjects died nevertheless the treatment (exchange-transfusions infusions of citrulline and ornithine). The autoptical studies showed cerebral oedema and fatty degeneration of the liver. Hepatic and seric OTC activity was measured in three patients: enzyme activity was virtually absent in one patient and normal in the other two. Instead in one patient was found partial CPS deficiency. However, Reye's syndrome is not only correlated with enzymatic deficiency of urea's cycle but sometimes also with toxic and metabolic causes.

Neurogenic pulmonary edema and variations of hemodynamic volumetric parameters in children following head trauma.

BACKGROUND: Currently there is no clear evidence of how changes in hemodynamic parameters are involved in the onset of neurogenic pulmonary edema. Aim of the study has been to correlate the principal variations of the intracranial pressure and volumetric hemodynamic parameters with the variations of extravascular lung water following severe head trauma in children. METHODS: We studied 28 children, 16 males and 12 females, mean ± SD age 71±29 months (range 24-130 months), admitted for traumatic head injury with Glasgow Coma scale ≤8. All patients received volumetric hemodynamic, and intracranial pressure monitoring following initial resuscitation and every four hours thereafter or whenever a hemodynamic deterioration was suspected. All readings were divided in 2 groups: with intracranial pressure (ICP) >15 mmHg or ≤15 mmHg. RESULTS: During the cumulative in hospital stay a total 508 sets of measurements were done. In the group with ICP >15 mmHg vs. that with ICP ≤15 mmHg we observed increased Extravascular Lung Water Index (EVLWi) (11.05±2.28 vs. 6.96±0.87 P<0.0001) and pulmonary permeability (8.50±1.19 vs. 5.08±0.90, P<0.0001), and decreased systemic vascular resistances, (1,451±371 vs. 1,602±447 P<0.0001) cerebral perfusion (48.87±18.67 vs. 69.72±11.36 P<0.0001) and PaO2/FiO2 ratio (349±122 vs. 490±96 P<0.0001). There was a significant correlation between EVLWi and pulmonary permeability (R2=0.83, P<0.0001). Fluid overload and cardiac functional index did not change significantly. CONCLUSION: The increased EVLWi observed in children following severe head trauma seems mainly related with pulmonary vascular permeability which is significantly increased when ICP is >15 mmHg.