TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases

The TP53 (p53) pathway can be inhibited by TP53 mutation or deletion or by MDM2 overexpression. Both occur in Burkitt lymphoma (BL), but many cases lack either abnormality. Expression patterns of the TP53 inhibitor MDM4 have not been reported in BL, and increased MDM4 could deregulate the TP53 pathway in cases without TP53 or MDM2 abnormalities. We investigated TP53 pathway disruption in paediatric BL patient samples (n = 30) by studying MDM4, MDM2, and CDKN1A (p21) protein and mRNA expression; TP53 mutations; TP53 protein expression; and gene copy number abnormalities. MDM4 protein was expressed in 30/30 tumours, and MDM2 protein was weakly expressed in 7/30 (23%). All cases were negative for CDKN1A protein, and CDKN1A mRNA levels were decreased. TP53 mutations were detected in 5/28 (18%) cases and confirmed by sequencing. TP53 protein was expressed in 15/30 (50%) cases, including 7/8 with TP53 genetic alterations. MDM2 protein and mRNA expression levels did not correlate with lack of TP53 genetic changes or TP53 protein expression; however, there was an inverse relationship between detectable TP53 protein expression and MDM4 copy number gains and mRNA expression. The TP53 pathway is deregulated in paediatric BL cases, and increased MDM4 expression may be the primary mechanism in some cases.     

Adipokines levels are associated with the severity of liver disease in patients with alcoholic cirrhosis

AIM:To investigate the adipokine levels of leptin,adiponectin,resistin,visfatin,retinol-binding protein 4(RBP4),apelin in alcoholic liver cirrhosis(ALC).METHODS:Forty non-diabetic ALC patients[median age:59 years,males:35(87.5%),Child-Pugh(CP)score:median 7(5-12),CP A/B/C:18/10/12,Model for End-stage Liver Disease(MELD):median 10(6-25),follow-up:median 32.5 mo(10-43)]were prospectively included.The serum adipokine levels were estimated in duplicate by ELISA.Somatometric characteristics were assessed with tetrapolar bioelectrical impedance analysis.Pearson’s rank correlation coefficient was used to assess possible associations with adipokine levels.Univariate and multivariate Cox regression analysis was used to determine independent predictors for overallsurvival.RESULTS:Body mass index:median 25.9(range:20.1-39.3),fat:23.4%(7.6-42.1),fat mass:17.8(5.49-45.4),free fat mass:56.1(39.6-74.4),total body water(TBW):40.6(29.8-58.8).Leptin and visfatin levels were positively associated with fat mass(P0.001/P=0.027,respectively)and RBP4 with TBW(P=0.025).Median adiponectin levels were significantly higher in CPC compared to CPA(CPA:7.99±14.07,CPB:7.66±3.48,CPC:25.73±26.8,P=0.04),whereas median RBP4 and apelin levels decreased across the spectrum of disease severity(P=0.006/P=0.034,respectively).Following adjustment for fat mass,visfatin and adiponectin levels were significantly increased from CPA to CPC(both P0.001),whereas an inverse correlation was observed for both RBP4 and apelin(both P0.001).In the multivariate Cox regression analysis,only MELD had an independent association with overall survival(HR=1.53,95%CI:1.05-2.32;P=0.029).CONCLUSION:Adipokines are associated with deteriorating liver function in a complex manner in patients with alcoholic liver cirrhosis.     

The role of advanced glycation end products in retinal microvascular leukostasis

PURPOSE. A critical event in the pathogenesis of diabetic retinopathy is the inappropriate adherence of leukocytes to the retinal capillaries. Advanced glycation end-products (AGEs) are known to play a role in chronic inflammatory processes, and the authors postulated that these adducts may play a role in promoting pathogenic increases in proinflammatory pathways within the retinal microvasculature. METHODS. Retinal microvascular endothelial cells (RMECs) were treated with glycoaldehyde-modified albumin (AGE-Alb) or unmodified albumin (Alb). NFkappaB DNA binding was measured by electromobility shift assay (EMSA) and quantified with an ELISA. In addition, the effect of AGEs on leukocyte adhesion to endothelial cell monolayers was investigated. Further studies were performed in an attempt to confirm that this was AGE-induced adhesion by co-incubation of AGE-treated cells with soluble receptor for AGE (sRAGE). Parallel in vivo studies of nondiabetic mice assessed the effect of intraperitoneal delivery of AGE-Alb on ICAM-1 mRNA expression, NFkappaB DNA-binding activity, leukostasis, and blood-retinal barrier breakdown. RESULTS. Treatment with AGE-Alb significantly enhanced the DNA-binding activity of NFkappaB (P = 0.0045) in retinal endothelial cells (RMECs) and increased the adhesion of leukocytes to RMEC monolayers (P = 0.04). The latter was significantly reduced by co-incubation with sRAGE (P < 0.01). Mice infused with AGE-Alb demonstrated a 1.8-fold increase in ICAM-1 mRNA when compared with control animals (P < 0.001, n = 20) as early as 48 hours, and this response remained for 7 days of treatment. Quantification of retinal NFkappaB demonstrated a threefold increase with AGE-Alb infusion in comparison to control levels (AGE Alb versus Alb, 0.23 vs. 0.076, P < 0.001, n = 10 mice). AGE-Alb treatment of mice also caused a significant increase in leukostasis in the retina (AGE-Alb versus Alb, 6.89 vs. 2.53, n = 12, P < 0.05) and a statistically significant increase in breakdown of the blood-retinal barrier (AGE Alb versus Alb, 8.2 vs. 1.6 n = 10, P < 0.001). CONCLUSIONS. AGEs caused upregulation of NFkappaB in the retinal microvascular endothelium and an AGE-specific increase in leukocyte adhesion in vitro was also observed. In addition, increased leukocyte adherence in vivo was demonstrated that was accompanied by blood-retinal barrier dysfunction. These findings add further evidence to the thinking that AGEs may play an important role in the pathogenesis of diabetic retinopathy.     

Skin diseases in Greek and immigrant children in Athens

Objectives This study aimed to characterize the spectrum of skin diseases affecting children in Greece. Methods We retrospectively studied data for 4071 children, aged 0–12 years, who were examined and diagnosed with dermatoses at the outpatient clinic of a university dermatological hospital between December 2005 and August 2007. To evaluate changes in disease patterns, these data were compared with data for a cohort of 12,700 children diagnosed with skin diseases at the same clinic two to three decades earlier (in 1977, 1980, and 1983). Results The most frequent disease was dermatitis/eczema (34.7%), with atopic dermatitis found in 20.7% of children, contact dermatitis in 6.9%, pityriasis alba in 2.1%, and seborrheic dermatitis in 1.8%. Infections (19.3%), nevi (5.6%), scabies (4.8%), and insect bites (4.3%) followed. More viral (12%) than bacterial (3.7%) and fungal (3.6%) infections were noted. Warts constituted 53.2% of viral infections. Immigrants had an increased risk for bacterial infections and scabies. Conclusions Children diagnosed with skin diseases 24–30 years earlier were younger; exhibited lower prevalences of dermatitis/eczema (P = 0.01), viral infections (P < 0.001) and nevi (P < 0.001); higher prevalences of bacterial and fungal infections (P < 0.001) and insect bites (P < 0.01); and similar rates of scabies (P = 0.17). This study documents the high prevalence of atopic dermatitis in the region, the increasing incidence of viral infections and nevi, and the continuing problem of scabies, especially in immigrants.     

The Home Observation for Measurement of the Environment Revisited

This review describes the Home Observation for Measurement of the Environment (HOME). After describing the structure of the instrument, it shows how it has been used successfully in studies on normally developing children and on samples drawn from high-risk populations. These are followed by studies showing how the HOME has been used to evaluate interventions. Although most interventions are not designed primarily on the basis of the HOME outcomes, the instrument has been used as a measure of the effectiveness of the intervention schedule. HOME has been used extensively in research to reveal relationships between several aspects of the home environment and children's developmental outcomes. The very good relationship between HOME scores and children's measures of developmental competence has also been found in non-normative populations and research has attempted to identify the specific aspects of the home environment, as indexed by the HOME subscales that reveal the strengths or the weaknesses of homes of at-risk populations.     

Unusual familial presentation of epsilon‐sarcoglycan gene mutation with falls and writer's cramp

Inherited myoclonus dystonia (M‐D, DYT11) is an autosomal dominant dystonia‐plus syndrome, which in many families is caused by mutations in the SGCE/ (epsilon‐sarcoglycan gene. We present a family with M‐D, with an unusual presentation characterized by infantile onset with falls in two sisters and adult‐onset writer's cramp in their father. Myoclonus dystonia is typically characterized by a variable mixture of alcohol‐sensitive myoclonic jerks and dystonia classically affecting mainly the proximal arms and neck. Leg involvement is less frequent, and to our knowledge, initial presentation with falls has not previously been described. The unusual phenotype of the family is discussed. © 2008 Movement Disorder Society.     

Mycobacterium tuberculosis transmission among high school students in Greece

BACKGROUND: The aim of this study was to investigate the requirements and practical steps for screening of Mycobacterium tuberculosis (MTB) transmission among high school student populations in two regional high schools of central Greece. Case-matched control populations from other regional schools were included. METHODS: Case study of two indexed cases, 61 close contacts, 212 casual contacts and 369 controls were investigated. Detailed questionnaires, tuberculin-skin test (PPD test), chest radiography, medical evaluation and DNA fingerprinting of sputum isolates were used. RESULTS: In case A, three (1.97%) of 152 close and casual contacts developed tuberculosis, and a further 25 (16.4%) were classified as infected. In contrast, none of the 121 close or casual contacts investigated for Case B developed tuberculosis or were classified as infected. None of the control populations contained infected individuals. Contacts of case A had a much higher risk (3.08 < RR = 22.29 < 161.69, P < 0.001) of being infected than contacts of case B. Two different strains of MTB were found responsible for these outbreaks. CONCLUSION: There was a considerable difference in the infectivity of the two cases presumably due to environmental and clinical factors, although two different MTB strains were responsible. It is proposed that the extent of case investigation should be individualized with particular emphasis placed among close contacts.     

A transversal pilot study of oropharyngeal carriage of <Emphasis Type="Italic">Kingella kingae</Emphasis> in healthy children younger than 6 months

Background

The aim of this pilot study was to investigate the extent of oropharyngeal Kingella kingae carriage during the first 6 months of life.

Methods

We conducted a monocentric transversal pilot study on healthy children younger than 6 months in order to define the oropharyngeal carriage rate. Participants were recruited between December 2013 and September 2015 among children without symptoms or signs of invasive infections.

Results

We demonstrated an oropharyngeal carriage rate of 0.67% in children younger than 6 months. Due to the really low carriage rate, it was not possible to draw statistically significant conclusion about any other characteristic of our population.

Conclusions

The present study suggests that the oropharyngeal carriage of Kingella kingae among a Swiss population of healthy infants younger than 6 months is exceptional. The scarcity of colonization and disease in the early months of life suggests thus that defense against mucosal carriage and invasive infection is above all provided by vertically acquired immunity. Limited exposure of the neonates due to limited social contacts may also represent another factor avoiding neonates’ mucosal Kingella kingae carriage.