Tetraspanin CD82 regulates bone marrow homing of acute myeloid leukemia by modulating the molecular organization of N-cadherin.

Communication between acute myeloid leukemia (AML) and the bone marrow microenvironment is known to control disease progression. Therefore, regulation of AML cell trafficking and adhesion to the bone marrow is of significant interest. In this study, we demonstrate that differential expression of the membrane scaffold CD82 modulates the bone marrow homing of AML cells. By combining mutational analysis and super-resolution imaging, we identify membrane protein clustering by CD82 as a regulator of AML cell adhesion and bone marrow homing. Cluster analysis of super-resolution data indicates that N-linked glycosylation and palmitoylation of CD82 are both critical modifications that control the microdomain organization of CD82 as well as the nanoscale clustering of associated adhesion protein, N-cadherin. We demonstrate that the inhibition of CD82 glycosylation increases the molecular packing of N-cadherin and promotes the bone marrow homing of AML cells. In contrast, we find that the inhibition of CD82 palmitoylation disrupts the formation and organization of N-cadherin clusters and significantly diminishes bone marrow trafficking of AML. Taken together, these data establish a mechanism where the membrane organization of CD82, through specific posttranslational modifications, regulates N-cadherin clustering and membrane density, which impacts the in vivo trafficking of AML cells. As such, these observations provide an alternative model for targeting AML where modulation of protein organization within the membrane may be an effective treatment therapy to disrupt the bone marrow homing potential of AML cells.

A controlled multicenter pediatric study in the treatment of acute respiratory tract diseases with the aid of a new specific compound, erdosteine (IPSE, Italian Pediatric Study Erdosteine).

INTRODUCTION: Erdosteine is an original drug which has been suggested as secretolytic compound and promoter of respiratory ventilation in the treatment of acute and chronic respiratory diseases. Moreover, the drug possesses also scavenging, antioxidant, and bacterial anti-adhesivity properties. From a clinical point of view the best results have been obtained by combined treatment with an antibiotic agent of useful spectrum activity. Aim of the present study was to evaluate the improvement induced in the risk/benefit ratio by erdosteine on the broad-spectrum antibiotic (ampicillin) in the treatment of acute lower respiratory tract diseases in the pediatric field. MATERIAL AND METHODS: A controlled multicenter double-blind parallel group trial was planned comparing erdosteine, supplied as syrup 3.5% or as sachets 225 mg, versus the relevant placebo. The tested compounds were administered in association with ampicillin. Two-hundred (n = 200) subjects entered the trial, randomly selected among patients monitored by the different centers, and were assigned to one of the treatments under evaluation, i.e. active compound or placebo with the aim to constitute two comparative homogeneous groups of 100 subjects each. Subsequently each group was again divided according to age in two equivalent subgroups of 50 patients each and treated with the syrup 3.5% (age from 2 to 4 years) or the sachet form (age from 5 to 10 years). The treatments administered in the two comparison groups were erdosteine (syrup 3.5% and 225 mg sachets) or the relevant placebo. The erdosteine posologies were adapted according to age. The lower dosage of the 5-10 years range in comparison with the 2-4 years range was established on the base of bioavailability characteristics of the two pharmaceutical forms. In all groups ampicillin was administered at the dosage of 100 mg/kg/day, according to a b.i.d. time schedule. The primary efficacy criterion was the cough score evaluated in a subjective way and expressed with the following scores: 1 = absent; 2 = mild; 3 = moderate; 4 = severe. The secondary efficacy end-points were: body temperature (expressed in degrees C); the polypnea, ronchi and rales estimation with a rating scale similar to that previously mentioned. These parameters were determined before starting of the treatment (VO); at the 3rd +/- 1 (V1) and at the 7th +/- 2 (V2) day of treatment. The body temperature was measured orally in the morning at awakening time with a mercury thermometer. Obtained data expressed in Celsius degrees are recorded by the investigator in the patient file during control visits. The safety of adopted treatments was evaluated with two different approaches. The clinical part was determined with the adverse drug reactions (ADRs) estimate. The biological safety was estimated at admission day (day 0) and at the final visit by means of a sophisticated statistical approach. RESULTS: The final results were the following: Erdosteine syrup 3.5%: concerning cough (primary end-point) in the group of patients (n = 50) treated with erdosteine it has been possible to point out a reduction of 23.8% at V1, i.e. after 3+/-1 days, and of 59.8% at V2, i.e. after 7+/-2 days. In the group of patients treated with placebo (n = 50) the reduction has been of 20.1% at V1 and of 36.6% at V2. The statistical analysis evidenced p values < 0.01 for times, treatments, time x treatments. The relevant results are summarized in Table 2. Erdosteine sachets 225 mg: concerning cough (primary end-point) in the group of patients (n = 50) treated with erdosteine it has been possible to point out a reduction of 17.6% at V1, i.e. after 3+/-1 days, and of 56.8% at V2, i.e. after 7+/-2 days. In the group of patients treated with placebo (n = 50) the reduction has been of 15.6% at V1 and of 31.8% at V2. The statistical analysis evidenced p values < 0.01 for times, treatments, time x treatments. (ABSTRACT TRUNCATED)

[The validity of screening for hypertension in school-age children. A cross-sectional study of a sample of 861 pupils of the towns of Local Health Unit No. 22 of Vittoria (Sicily)]. / Validità dello screening per ipertensione in età scolare. Studio trasversale su un campione di 861 alunni dei comuni dell'U.S.L. 22 di Vittoria (Sicilia).

In order to define the validity of a screening program for hypertension in schools, aiming to prevent an hypertensive status in adult age, we screened 861 children from schools on the area of our Medical District (U.S.L. 22--Vittoria--Sicily). The object of our study is to search for risk factors of hypertension, detectable at school age and, if existing, which age is more suitable for a screening program. We randomly sampled 861 children from different schools, aging 6, 10 and 13 years. The first step was to define the prevalence of hypertension and obesity in the sample, and the correlation between the two factors (transversal study). We found an overall prevalence of obesity at 6, 10, and 13 years of 6.69%, 18.22% and 17.7% respectively. The prevalence of hypertension was 4.01%, 11.4%, and 6.98% at 6, 10 and 13 years respectively. The second step is to create a personal record of each child, which will be followed up to the age of 18 years, containing familial and nutritional informations, periodic evaluations of height, weight, blood pressure and biologic sampling (longitudinal study). Our preliminary results confirmed the correlation between obesity and hypertension, although they do not help to clarify why the prevalence of hypertension decreases from 10 to 13 years whereas obesity maintains the same prevalence at the mentioned ages.

[Hemangioendothelioma of the liver in the newborn: description of 2 cases]. / Emangioendotelioma del fegato in età neonatale: descrizione di due casi.

The infantile hemangioendothelioma of the liver is a rare benign vascular tumor that accounts for some 10% of all primary hepatic masses. Two cases were seen at the Department of Pediatric Surgery of Vicenza's Hospital in the last ten years. Both of patients were females and presented in neonatal period asymptomatic. The first patient was found to have hepatomegaly by pediatrician at six weeks of age, the second was an incidental finding following ultrasound neonatal screening. The Authors outline some difficulties met with differential diagnosis between benign versus malignant hepatic tumors. Explorative laparotomy was considered necessary in both the patients. Liver biopsy was the only surgical procedure performed in the nonresectable tumor. Treatment with corticosteroids finally proved to be successful to determine progressive involution of the tumor. In the resectable form, left hepatic lobectomy was successfully performed because of the progressive size increase of the tumor.

[Free autogenous muscle grafts in nine children with total and incontinence (author's transl)]. / Autotrapianto muscolare libero in nove bambini con incontinenza anale totale.

Nine children with total anal incontinence after surgery for anorectal agenesis were successfully operated on by free autogenous muscle transplantation. Skeletal muscles were first denervated and 3 weeks later transplanted to the anal region as a U--sling around the rectum, imitating the normal position and function of the puborectalis muscle. The grafts were placed in contact with the normal muscles of the region to make reinnervation possible. Eight children were completely evaluated after operation. Two years after surgical procedure six children were "continent" and only two were still incontinent, but improved. In these cases the indication for muscle transplantation was not quite correct. The return of the function of the muscle grafts completely changed the lives of these children. The results of this new surgical procedure are encouraging and invite further trials.