Magnetic resonance imaging screening of cerebral thromboembolic events in children with acute lymphoblastic leukemia: a pilot study.

BACKGROUND: Thromboembolism is a complication of acute lymphoblastic leukemia therapy in children. The majority of thromboembolic events are cerebral thromboses and deep venous thromboses; many asymptomatic deep venous thromboses are detected in children with acute lymphoblastic leukemia by instrumental screening. The aim of this study was to assess the incidence of asymptomatic cerebral thromboembolic events in children with acute lymphoblastic leukemia (ALL) screened by magnetic resonance imaging and magnetic resonance venography. METHODS: 46 children with acute lymphoblastic leukemia, during the induction phase of the AIEOP ALL 2000 protocol, were stratified into 2 groups. In group "A" cerebral thromboembolic events were suspected following the appearance of suggestive signs and symptoms and confirmed by cerebral magnetic resonance imaging and magnetic resonance venography; in group "B" children underwent a screening by cerebral magnetic resonance imaging and magnetic resonance venography, at set times, in absence of symptoms. RESULTS: We observed one cerebral thromboembolic event in both groups; we found no differences between early detecting asymptomatic cerebral thromboembolic events among monitored and not monitored patients. CONCLUSIONS: Our study does not seem to suggest a screening for asymptomatic cerebral thromboembolic events in children with ALL during the induction phase.

Thyroid function and thyroid autoimmunity in childhood acute lymphoblastic leukemia off-therapy patients treated only with chemotherapy.

OBJECTIVE: Scanty data are available about the thyroid function in childhood acute lymphoblastic leukemia (ALL) off-therapy patients treated only with chemotherapy. We aimed to assess the prevalence of thyroid autoimmunity and thyroid dysfunction in such patients. DESIGN: Case-control cross-sectional study. METHODS: Eighty-four patients diagnosed with ALL and treated only with chemotherapy. Mean age at diagnosis 5.9+/-3.6 yr, at recruitment 12.1+/-4.3 yr. The treatment had been stopped 4.3+/-3.2 yr before recruitment. A control group of 60 subjects was recruited. Free T4, TSH, anti-thyroperoxidase, and anti-thyroglobulin antibodies were measured. RESULTS: Anti-thyroglobulin and anti-thyroperoxidase antibodies were negative in all patients. TSH was increased in 7 patients (8.3%) and 3 controls (5.0%). Free T4 was within the normal limits in all patients and controls.Mean TSH and free T4 levels did not statistically differ between controls and ALL offtherapy patients. TSH was negatively correlated with the age at the diagnosis (p=0.01) and the age at the end of therapy (p=0.008). Anti-thyroglobulin and/or anti-thyroperoxidase antibodies were detected in 3 controls (5%; vs study group: p=0.038), 1 of them with increased TSH. CONCLUSIONS: Some patients present hyperthyrotropinemia, without anti-thyroid antibodies, with a prevalence comparable to the control group. The thyroid gland seems more prone to be damaged by chemotherapy at a younger age. We think that a thyroid follow- up in ALL off-therapy patients may be advisable and should be differentiated on the basis of the age at the end of treatment, with more frequent tests for younger patients.

Growth hormone deficiency and antipituitary antibodies in a patient with common variable immunodeficiency.

Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and T-lymphocytes dysfunction. Autoimmune diseases are frequent. A 10.7-yr-old female, diagnosed with CVID when 7 yr old, was referred because of short stature. She was pre-pubertal and short (height -2.86 SD score) with delayed bone age. Her intestinal absorption, routine biochemistry, heart, renal, liver, and thyroid functions were normal. Two stimulation tests for GH showed a maximum peak of 1.9 ng/ml (IGF-1: 154 ng/ml, 147-832). When the patient was 13 yr old (height -4.23 SD score, telarche and pubarche stage 2, bone age 6.25 yr), GH treatment was initiated. Despite poor compliance, the growth velocity showed improvement. Anti-thyrogobulin, anti-thyroperoxidase, anti-21-hydroxylase, and anti-tyrosine-phosphate antibodies were negative while anti- pituitary antibodies (APA) were positive. For the first time, the presence of APA (previously associated with GH deficiency in non-CVID subjects) is reported in a CVID patient. The possibility of an autoimmune involvement of the pituitary gland was previously debated for CVID patients, but had never been demonstrated. This case suggests that in CVID, the pituitary gland can be targeted by autoantibodies and thus a more comprehensive follow-up of these patients should be performed.

Screening for children from families with Rendu-Osler-Weber disease: from geneticist to clinician.

BACKGROUND: Rendu-Osler-Weber syndrome, or hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant vascular disorder. The syndrome is characterized by telangiectases and arteriovenous malformations (AVMs) affecting skin, mucosae and internal organs. AVMs often remain clinically silent until provoking sudden serious complications, responsible for important morbidity and mortality which can occur both in adulthood and in children. The incidence of AVMs in HHT pediatric populations is unknown. OBJECTIVE: To describe the screening protocol performed in the first genotypically confirmed HHT pediatric population and to estimate the incidence of occult brain, lung and liver AVMs and the different disease phenotypes. MATERIALS AND METHODS: Molecular analysis was performed on 35 children, both symptomatic and asymptomatic, who were family members of probands with a previously identified mutation. Clinical-instrumental examination was performed on the mutation positive cases. Nasal telangiectases were investigated by anterior rhinoscopy. Contrast echocardiography and high resolution thoracic multislice computed tomography (CT) were performed to detect pulmonary arteriovenous malformations (PAVMs), and echo-color Doppler, and abdominal CT to detect hepatic arteriovenous malformations (HAVMs). Brain magnetic resonance imaging was utilized to detect cerebral angiopathic involvement. RESULTS: Molecular analysis demonstrated the mutation-carrier status in 22/35 children. Nineteen children, 12 of whom had epistaxis, positive to molecular testing underwent clinical evaluation. Nasal teleangiectases were found in 68%, mucocutaneous telangiectases (fingers, lips and oral cavity) in 79%, PAVMs in 53%, HAVMs in 47% and cerebral anteriovenous malformations and/or cerebral ischemic changes secondary to PAVMs in 12%. CONCLUSIONS: We evidenced a high incidence of HHT children with occult visceral lesions suggesting that a diagnostic screening may be indicated to appropriately treat brain and lung malformations.

HHT in childhood: screening for special patients.

Hereditary hemorrhagic telangiectasia (HHT) or the Rendu-Osler-Weber disease is a systemic fibrovascular autosomal dominant dysplasia, recognised when three of the following four clinical manifestations are present, according to the proposal of Shovlin.: recurrent nosebleeds, lelangiectasias of the skin, visceral lesions, and positive family history. HHT is often difficult to diagnose on the basis of history and physical examination alone, especially in infants and children. The signs and symptoms of HHT are nonspecific and are extremely variable within families. Given the frequent occurrence of clinically silent lesions in lung and brain arteriovenous malformations which can result in morbidity or death, much consideration should be given to screening patients with HHT for asymptomatic fistulae and to their treating once they are discovered. Presymptomatic interventions in such cases may substantially affect the outcome. It may be possible to state that lesions of HHT arise early in life, but do not reach sufficient size to cause symptoms until the second decade. Furthermore, as clinical manifestations often occur later in life, the development and the implementation of a molecular diagnosis will allow the identification of subjects with no evident signs of the disease but carrying the familial mutation. This is fundamental in order to establish reliable screening protocols for the prevention and cure of the disease and, to determine the presence of family members with no disease-associated mutation, who do not require further clinical screening.

Management of liver disease in thalassemia: main drug targets for a correct therapy.

Liver disease is the second cause of mortality in thalassemia major. We present a review on the hepatic damage in thalassemic patients aimed at a knowledge of current preventive, diagnostic and therapeutic approaches, useful to guide in clinical judgment and treatment decisions. Transfusion related iron overload and hepatitis are the causes of liver damage in thalassemic patients. We examined means of primary prevention, anti-hepatitis vaccinations, blood donors screening; diagnostic tests for secondary prevention (computed tomography, magnetic resonance imaging, super conducting quantum interference device and biopsy) were also discussed about. A survey of treatment methods and strategies ( chelation therapy, antiviral treatments and liver and bone marrow transplantation) follows.

Increased mononuclear cell tissue factor and type-2 plasminogen activator inhibitor and reduced plasma fibrinolytic capacity in children with lymphoma.

Blood clotting activation and fibrin deposition are common findings in lymphoma patients. We evaluated the capacity of peripheral blood mononuclear cells to produce procoagulant activity (PCA) and plasminogen activator inhibitor (PAI) in 12 children with newly diagnosed lymphoma (8 non-Hodgkin's, 4 Hodgkin's) and in 12 matched healthy donors. In the same subjects we also measured plasma antigen levels of tissue-type PA (t-PA), urokinase-type PA (u-PA), PAI-1, PAI-2, and D-dimer. PCA generated by mononuclear cells after incubation for 20 h at 37 degrees C was significantly higher in patients than in controls (p = 0.027). In all samples it was identified as tissue factor by functional criteria (dependence on factor VII). Moreover, culture medium obtained from patients' mononuclear cells after incubation for 20 h at 37 degrees C contained significantly higher amounts of PAI activity and PAI-2 antigen than control samples (p < 0.001). Plasma PAI-1 and t-PA antigens were significantly augmented in patients (p < 0.005), the mean increase of PAI-I being about 5 times higher than that of t-PA. Plasma levels of D-dimer were markedly increased in the patient's group (p < 0.001), whereas u-PA and PAI-2 antigens did not differ from controls. It is suggested that monocytes from lymphoma patients are endowed with functional abnormalities leading to the simultaneous expression of tissue factor and antifibrinolytic activity. These abnormalities, coupled with a reduced plasma fibrinolytic potential, could play an important pathogenetic role in blood clotting activation and fibrin deposition associated with lymphoma.

Unbalanced coagulation-fibrinolysis potential during L-asparaginase therapy in children with acute lymphoblastic leukaemia.

Treatment of acute lymphoblastic leukaemia (ALL) with L-asparaginase (L-asp) may be associated with thrombotic complications, but the pathogenetic mechanisms of thrombus formation and persistence remain unclear. We studied the procoagulant activity (PCA) of peripheral blood mononuclear cells and some components of the plasma fibrinolytic system in 10 children with ALL undergoing remission induction therapy which includes L-asp. Mononuclear cells obtained 14 days after starting L-asp treatment generated significantly higher amounts of PCA (identified as tissue factor) than cells isolated before the first dose of L-asp and 7 days after the cessation of L-asp administration (p less than 0.01). Augmented PCA coincided with an increase in the plasma D-dimer. The plasma levels of type 1 plasminogen activator inhibitor were found significantly elevated during L-asp therapy (p less than 0.05), whereas plasminogen levels were markedly decreased (p less than 0.05). These findings suggest that, during the course of L-asp treatment, the coagulation-fibrinolysis balance is shifted towards promotion of fibrin formation and deposition. Although it remains to be conclusively established whether L-asp per se or the concurrent administration of multiple chemotherapeutic agents is responsible for these changes, the latter could contribute to the thrombotic complications associated with remission induction therapy for ALL.

Age-specific prevalence of hepatitis B virus infection among children in an endemic area in southern Italy.

In 1989 the prevalence of hepatitis B virus markers was studied by radioimmunoassay in a sample of 1,426 healthy children, 3 to 11 years old, attending kindergarten and the primary schools in a large urban area of the Apulia Region in Southern Italy, where the hepatitis B surface antigen (HBsAg) prevalence among pregnant women is 5.6%. The overall prevalence of any hepatitis B virus marker was 3.4%, increasing from 1.7% in 3- to 5-year-old children to 5% in 10- to 11-year-old children (P less than 0.002). Prevalence was not associated with the father's years of schooling (odds ratio, 1.98; confidence interval, 95% (0.9 to 4.6] or with the family size (odds ratio, 2.96; confidence interval, (0.7 to 11.8]. The overall HBsAg prevalence was 0.8, a rate that was lower than the 5.6% found in pregnant women. The finding of only 12 HBsAg-positive children of the 1,426 tested, despite 80 of them being born to HBsAg-positive carrier mothers (on the basis of the 5.6% HBsAg prevalence among pregnant women), is probably attributable to the low proportion (5%) of hepatitis B e antigen positivity among the HBsAg-positive carrier mothers in the study area. The observed low HBV infection rate in younger age groups, which confirms recent studies in other areas of Italy, appears to be the result of several factors: improved socioeconomic conditions; decreased family size; and increased use of disposable syringes in the last few years.

Bone marrow transplantation in a case of severe, type II congenital dyserythropoietic anaemia (CDA II).

Type II congenital dyserythropoietic anaemia (CDA-II or HEMPAS) is an autosomal recessive disorder, representing the most frequent form of congenital dyserythropoiesis. It is characterised by normocytic anaemia, variable jaundice and hepato-splenomegaly. Gallbladder disease and secondary haemochromatosis are frequent complications. We report a case characterised by severe transfusion-dependent anaemia. The proband inherited CDA-II in association with beta-thalassaemia trait. Splenectomy did not abolish the transfusion dependence and this, in association with poor compliance to iron-chelation therapy, prompted us to consider bone marrow transplantation (BMT) from his HLA-identical sibling. The preparative regimen included busulfan, thiotepa and fludarabine, and graft-versus-host disease prophylaxis consisted of cyclosporin A and short-term methotrexate. Engraftment of donor cells was prompt and the post-transplant course uncomplicated. The patient is alive and transfusion-independent 36 months after allograft. This is the first case of severe CDA-II to undergo BMT. Analysis of this pedigree suggests that interaction with beta-thalassaemia enhanced the clinical severity of CDA-II, making BMT an attractive therapy for patients with transfusion dependence.

Reconstitution of normal neutrophil function in chronic granulomatous disease by bone marrow transplantation.

Allogeneic bone marrow transplantation was carried out on an 11-year-old boy with chronic granulomatous disease and severe chronic pulmonary insufficiency of restrictive type. After preparative regimen with busulfan (13 mg/kg) and cyclophosphamide (200 mg/kg), the patient received marrow cells from his HLA-identical and MLC-nonreactive sister. Durable sustained engraftment of donor hematopoietic and lymphoid populations occurred, as documented by analysis of genetic markers and complete reversal of the neutrophil function defect. No episode of infection occurred in the post-transplant course and, currently, 40 months after transplantation the patient is in excellent health and growing normally and showing an increasing improvement of his respiratory capacity. The successful outcome in this patient demonstrates that marrow transplantation is at present the only curative approach for this congenital disorder of neutrophil function.

Baseline sero-epidemiology of hepatitis B virus infection in children and teenagers in Italy. A survey before mass hepatitis B vaccination.

During the period May 1987 to November 1989, the prevalence of hepatitis B virus (HBV) markers was determined by ELISA in serum samples of 7405 (55% male, 45% female) apparently healthy persons 3-19 years of age in Italy. Earlier studies of adults there had shown an intermediate degree of HBV endemicity (hepatitis B surface antigen carrier rate greater than 2%). Persons were selected by systematic cluster sampling in five different geographical areas of Italy. The overall prevalence of hepatitis B surface antigen (HBsAg) was 0.6%. The overall prevalence of at least one marker of HBV was 2.8%; it increased from 1.7% among children 3-5 years of age to 4.5% in teenagers 17-19 years of age (P less than 0.001). The prevalence of any HBV marker was higher in southern then in northern areas (3.5% vs. 1.8%, P less than 0.001). A significant association was found with sociodemographic features. Persons whose fathers had less than 6 years of schooling had a 2.3-fold risk (C.I. 95% = 1.5-3.4) while those belonging to a household of six or more under one roof had a 1.7-fold risk (C.I. 95% = 1.2-2.4) of previous exposure to HBV infection. These findings indicate that, today in Italy, exposure to HBV infection at a young age is very low and suggest a shift towards a low degree of endemicity following improvements in socio-economic conditions, decreased family size and increasing use of disposable syringes during recent years.(ABSTRACT TRUNCATED AT 250 WORDS)

Association of congenital afibrinogenemia and K-dependent protein C deficiency--a case report.

The authors describe a rare case of congenital afibrinogenemia with concomitant K-dependent protein C deficit that was brought to our observation for ischemic lesions of the foot in association with fibrinogen concentrate infusions. These lesions can be attributed to the association of various factors: fibrinogen infusion without heparin coverage, microtrauma, and protein C (PC) deficit. In fact, thromboembolic complications during afibrinogenemia were previously reported usually in association with substitutive therapy, and it is also known that PC deficit predisposes to thrombotic complications. The the authors' knowledge, the case described by them is the first in which PC deficit is associated with afibrinogenemia. This association cannot be explained by a common genetic mechanism because the genes for fibrinogen and for protein C are located on different chromosomes (chromosomes 4 and 2 respectively).

Streptococcus pneumoniae nasopharyngeal colonization in young healthy children: rate of carriage, serotype distribution, and antibiotic resistance.

The nasopharyngeal colonization rate of Streptococcus pneumoniae and its antibiotic susceptibility was determined in a given population of 317 young children (ages 1-7 years) in the area of Bari, Italy. 18.29% of the cultures were positive for S. pneumoniae. 8.62% of the strains were intermediately resistant to penicillin. Erythromycin-(65.51%) and cotrimoxazole-(17.24%) resistance was also observed whereas all the strains resulted uniformely susceptible to cefotaxime and ceftriaxone. The high rate of nasopharyngeal carriage of Streptococcus pneumoniae along with the resistance to antibiotics widely used in the community suggests the importance of epidemiological surveillance as well as the application of new vaccine strategies.

[Antithrombin III assay using a chromogenic substrate in newborns]. / Il dosaggio dell'antitrombina III con substrato cromogenico nell'eta' neonatale.

The assay of antithrombin III activity (AT-III) was performed by chromogenic synthetic substrate in 42 full-term newborns, 1 to 7 days aged. AT-III levels were lower than normal adults in the first day of life and lessened again in the 3rd day. After this period the levels of AT-III rose slowly and in the 7th day were about half the concentration of adults.

Lymphadenopathy syndrome and HIV infection in multitransfused beta-thalassemia child.

Lymphoadenopathic Syndrome (LAS), diagnosed also with histologycal studies, is described in a polytransfused 11-year old boy affected by beta-thalassemia major. After three days of the admission he suffered a serious acute diarrhea by Aeromonas hydrophila, an opportunistic enteric bacteria demonstrated, up to date, in immunocompromised patients and never in AIDS patients. It is important to remark that beta-thalassemic patients are at high risk from HIV infections, either for the chronic need of transfusions and for the impairment of the immunological functions.

[Pediatric suspensions of amoxicillin and clavulanic acid in the treatment of bacterial infections of otorhinolaryngologic importance and the upper respiratory tract]. / Amoxicillina ed acido clavulanico in sospensione pediatrica nel trattamento di infezioni batteriche di pertinenza otorinolaringoiatrica e delle prime vie aeree.

Thirty children, 20 males and 10 females, aged 6.57 +/- 0.78 on the average (range: from 13 to 6 months), weighing 21.60 +/- 2.25 kg with bacterial infections of the upper respiratory tract and ear were admitted to the present trial. A chemotherapeutic agent based on amoxycillin and clavulanic acid in the suspension for children of 312.5 mg/5 ml (4:1 ratio) at the dosage of about 17 mg/kg in two daily administrations according to the weight of the patients was used. The therapy was prolonged for 8.87 +/- 0.30 days on the average, from a minimum of 3 to a maximum of 11 days. In the course of the treatment the symptom parameters and the objective signs progressively reduced until disappearance; the body temperature came promptly back to normal values, confirming the definite improvement and the regression of the infectious pictures. The microbiological data also fully confirmed the successful activity of the chemoantibiotic drug used. No side effects were found and, as regards local and general tolerance, no signs of an even slight impairment related to the administration of the drug were found. The final judgement expressed on the efficacy, on the basis of the more or less quick and complete symptom regression, evolution of the infectious picture and good tolerance were the following: excellent in 22 cases, good in 6, fair in 1 and not able to be evaluated in 1 case (a female patient who left off the trial).

Post-natal development of factor II (pre-prothrombin and prothrombin) in man.

Postnatal development of factor II molecule has been evaluated by three different methods in infants and children from 15 days to 7 years of age. The immunochemical determination of factor II showed that the plasma levels of this factor reached the lowest adult values between 4-7 months of age and rose slowly for all the first year; after this age the plasma concentration was steady. The adult range was reached from 15 to 120 days of age when the factor II was evaluated by the method of Owren and Aas (19) and by staphylocoagulase reagent.

Post-natal development of factor IX.

Post-natal development of clotting activity and of antigen level of Factor IX was evaluated in 111 healthy, breastfed, newborn infants, aged 1-30 days. Of these, 80 had received at birth 2 mg of vitamin K1 orally. Factor IX clotting activity was determined by one-stage assay and antigen level by electroimmunoassay. On the 1st day both antigen level and clotting activity were low and the ratio was 1.01. There was a significant postnatal increase of the two activities of Factor IX during the first three days of life; thereafter both remained constant. No statistical difference inFactor IX activity was found with oral administration of vitamin K1 after the birth. During the first month of life both clotting activity and antigen level of Factor IX were low as compared to adult values. There was no correlation with age. The Factor IX protein of newborns did not show molecular heterogeneity by crossed-immunoelectrophoresis.