Pediatric transplantation in Europe during the COVID-19 pandemic: Early impact on activity and healthcare

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families.     

Frequency of the HFE gene mutations in five Italian populations

Genetic hemochromatosis is an autosomal recessive disorder characterized by iron overload and a variety of clinical manifestations such as liver cirrhosis and arthropathy. It is the most common genetic disease of northern European populations. The principal gene responsible for hereditary hemochromatosis, designated HFE, is located on chromosome 6 in the HLA region. The single point mutation 845A, changing cysteine at position 282 to tyrosine (C282Y), in this gene has been identified as the main genetic basis of hereditary hemochromatosis. Two other mutations, 187G, a histidine to aspartate at amino acid 63 (H63D), and 193T, a serine to cysteine at amino acid 65 (S65C), appear to be associated with milder forms of hereditary hemochromatosis. There is a high prevalence of the C282Y mutation in northern European populations, whereas in those of the Mediterranean basin the prevalence seems low and almost absent in Far East countries. This mutation seems usually to occur on the ancestral haplotype 7.1. Accordingly, a Celtic origin of this mutation has been suggested. The aim of this study was to determine the frequency of HFE gene mutations in five geographic regions in Italy. Samples were tested for C282Y, H63D, and S65C mutations of the HFE gene according to methods of each laboratory and the results were standardized with the exchange of typed samples between the different laboratories. In addition, C282Y-positive DNA samples were typed for D6S105 allele 8 and HLA-A3 by ARMS-PCR. We have found that the allele frequency of the C282Y mutation decreases from northeast Italy (Friuli, 6%) to northwest Italy (Piedmont, 4.8%) and to central Italy (Emilia-Romagna, 1.7%). However, this mutation is lacking in the two regions of the Mediterranean basin's center (Sicily and Sardinia). Accordingly, a significant difference in the frequency of the mutation was observed between these Italian regions (P = 0.07 x 10(-3)). In contrast, no difference was observed in allele frequency of H63D in the five Italian regions. Finally, as regards the S65C mutation a very low frequency was observed in Friuli, Emilia-Romagna, and Sardinia, whereas in Sicily and Piedmont we have not found this mutation. In conclusion, these data are consistent with the hypothesis that the C282Y mutation occurred in Caucasian populations of Celtic origin, whereas the H63D mutation is more ancient as demonstrated by the ubiquitous distribution.     

Severe hyperglycemia: a determinant factor for hypofiltration in alloxan diabetic rats

Abstract. The relationships among glomerular filtration rate, renal plasma flow and extracellular fluid volume were investigated in control and severely hyperglycemic (442±33 mg/dl) untreated, alloxan diabetc rats. Most of diabetic animals showed significant lower values of inulin clearance (diabetics, 0.55±0.07 ml/min·100 g; controls, 0.97±0.04) and p-aminohippurate clearance (diabetics, 2.11±0.39 ml/min·100 g; controls, 3.93±0.25). Diabetic rats exhibited reduced efficiency in tubular Na⁺ reabsorption, increased urinary Na⁺ excretion (diabetics, 3.12±0.27 mEq/day; controls, 1.25±0.14) and diminished values of plasma renin activity (diabetics, 3.34±0.44 ng/ml·h; controls, 8.64±0.79). Significant negative correlations were found between glycemia and renal hemodynamic variables. Acute overload with glucose further decreased these variables in both groups: inulin clearance in diabetics vs. controls, 0.26±0.04 vs. 0.44±0.05 ml/min·100 g; p-aminohippuric acid clearance in diabetics vs. controls, 1.09±0.20 vs. 1.55±0.21 ml/min·100 g. We conclude that chronically hyperglycemic alloxan diabetic rats showed diminished glomerular filtration rates (inulin clearance), renal plasma flow (p-aminohippurate clearance) and extracellular fluid volume associated with urinary Na⁺ losses and alterations in the renin-angiotensin system. Decreased reninangiotensin system activity might reduce aldosterone secretion, which in turn could result in (succesively) urinary sodium loss, extracellular fluid volume contraction and reductions in glomerular filtration and renal plasma flow.     

Prnp gene and cerebellum volume in patients with refractory mesial temporal lobe epilepsy

The cellular prion protein, encoded by Prnp gene, is involved in neuroprotection, neuroplasticity and neurodevelopment. The variant allele Valine at codon 129 of the Prnp was associated with decreased brain volume in healthy volunteers and schizophrenic patients. We investigate the association between the cerebellum volume and the presence of variant allele Valine at codon 129 of the Prnp gene in patients with mesial temporal lobe epilepsy related to hippocampal sclerosis (MTLE-HS). The Prnp coding sequence was determined in 41 refractory MTLE-HS patients. The cerebellum volume corrected by the intracranial volume of patients with the normal Prnp genotypes was compared with that of patients presenting the variant alleles at codon 129. Twenty patients showed the Met129Met genotype, 16 showed Met129Val, and 5 had Val129Val. There were no association among clinical, demographic, electrophysiological, antiepileptic drugs used, and the presence of the Prnp variant alleles. The presence of Prnp variant allele at codon 129 was not associated with the analyzed cerebellum volume. Prnp variant alleles at codon 129 are not associated with cerebellum volume in patients with refractory MTLE-HS.     

Observational study of optimization of biologic therapies in rheumatoid arthritis: a single-centre experience

To analyse the effectiveness of optimization of biologics in rheumatoid arthritis (RA). It was a single-centre retrospective observational study from January 2009 to September 2012. The effectiveness of the optimization of TNF antagonists, tocilizumab and abatacept in RA was studied. Optimization included predefined dose down-titration and/or expansion of dose interval in early arthritis with sustained DAS28-ESR <2.6 and established arthritis with a sustained DAS28-ESR <3.2. Primary outcome was time to relapse defined as increase in DAS28-ESR greater than 20 % over baseline. Cox’s regression analysis was performed to identify predictors of relapse. Sixty-four patients were included in the study. In the survival analysis, rates of relapse were 9.8 % at 6 months, 31.4 % at 12 months and 44.6 % at 18 months. Rates of patients with an increase in DAS28-ESR > 20 % and ≥1 inflamed joint at 6, 9 and 18 months were 1.6, 17.2 and 27.1 %, respectively. In relapsing patients, mean DAS28-ESR at relapse was 3.44 (2.94–4.79) and mean DAS28-ESR following the return to the prior dose of the biologic was 2.52 (1.42–3.21). No predictors of relapse were found in multivariate analysis. Optimization of the treatment with biologics in RA is an efficacious and safe treatment option.     

Rare cause of abdominal incidentaloma: Hepatoduodenal ligament teratoma

The occurrence of a hepatoduodenal ligament teratoma is extremely rare,with only a few cases reported in the literature.This case report describes the discovery of a hepatoduodenal ligament lesion revealed during abdominal ultrasonography for cholelithiasis-related abdominal pain in a 27-year-old female.Cross-sectional imaging identified a 5 cm×4 cm heterogeneous mass of fat tissue with irregular calcification located in the posterior-superior aspect of the head of the pancreas.An encapsulated lesion showing no invasion to the common bile duct or adjacent organs and vessels was exposed during laparotomy and resected.Intraop-erative cholangiography during the cholecystectomy showed no abnormalities.The postoperative course was uneventful.Pathological analysis of the resected mass indicated hepatoduodenal ligament teratoma.This case report demonstrates that cross-sectional im-aging,such as computed tomography,can reveal sus-pected incidences of this rare type of teratoma,which can then be confirmed after pathologic analysis of the specimen.The prognosis after complete surgical resec-tion of lesions presenting with benign pathological fea-tures is excellent.     

Mucociliary clearance,airway inflammation and nasal symptoms in urban motorcyclists

OBJECTIVES:There is evidence that outdoor workers exposed to high levels of air pollution exhibit airway inflammation and increased airway symptoms. We hypothesized that these workers would experience increased airway symptoms and decreased nasal mucociliary clearance associated with their exposure to air pollution.METHODS:In total, 25 non-smoking commercial motorcyclists, aged 18-44 years, were included in this study. These drivers work 8-12 hours per day, 5 days per week, driving on urban streets. Nasal mucociliary clearance was measured by the saccharine transit test; airway acidification was measured by assessing the pH of exhaled breath condensate; and airway symptoms were measured by the Sino-nasal Outcome Test-20 questionnaire. To assess personal air pollution exposure, the subjects used a passive-diffusion nitrogen dioxide (NO₂) concentration-monitoring system during the 14 days before each assessment. The associations between NO₂ and the airway outcomes were analyzed using the Mann-Whitney test and the Chi-Square test. Clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT01976039","term_id":"NCT01976039"}}NCT01976039.RESULTS:Compared with clearance in healthy adult males, mucociliary clearance was decreased in 32% of the motorcyclists. Additionally, 64% of the motorcyclists had airway acidification and 92% experienced airway symptoms. The median personal NO₂ exposure level was 75 mg/m³ for these subjects and a significant association was observed between NO₂ and impaired mucociliary clearance (p = 0.036).CONCLUSION:Non-smoking commercial motorcyclists exhibit increased airway symptoms and airway acidification as well as decreased nasal mucociliary clearance, all of which are significantly associated with the amount of exposure to air pollution.     

Novel genetic markers of rheumatoid arthritis in chilean patients,by dr serotyping and restriction fragment length polymorphism analysis

Objective. The analysis of genetic markers of rheumatoid arthritis (RA) in a population in which the DR4 serotype is not strongly associated with the disease. Methods. Chilean RA patients (56 seropositive and 22 seronegative) and 141 controls were studied by serotyping. Southern blot analysis of Bam HI restriction fragment length polymorphism (RFLP) was done in genomic DNA from 46 patients with seropositive RA, 17 patients with seronegative RA, and 45 controls, using a complementary DNA probe specific for DRB1 genes. Results. The prevalence of the HLA—DR9 haplotype was strikingly higher in seropositive RA patients (21%) than in controls (3%) (P_corr < 0.0008, by Fisher's exact test; relative risk [RR] = 9.34). The prevalence of DR4 and DR1 haplotypes, although slightly increased, did not achieve a significant preponderance. The simultaneous presence of two Bam HI fragments (3.6 kb and 4.5 kb) was found with higher prevalence in seropositive patients (83%; RR = 9; P_corr < 0.00002) than in controls (36%), and seemed higher in seronegative RA patients as well (71%; RR = 4). Furthermore, its prevalence remained increased in comparisons of DR4 positive controls (36%) with DR4 positive seropositive patients (100%; RR = 67; P_corr < 0.0002) and DR4 positive seronegative patients (100%; RR = 36; P_corr < 0.006), even after excluding the DR9 positive individuals. A tendency toward higher association with DR1 seropositive RA patients (67%; RR = 12), a group with no DR4 or DR9 positive individuals, than in DR1 positive controls (14%), was also observed. Conclusion. The HLA—DR9 haplotype was definitively consolidated as a very strong genetic marker exclusively for seropositive RA in Chilean patients, as suggested by our previous observations. RFLP analysis showed that the simultaneous presence of 3.6-kb and 4.5-kb Bam HI fragments constituted a better RA marker than did any of the heretofore studied haplotypes. These fragments together would be linked to RA independently of the DR1, DR4, and DR9 haplotypes. The overall evidence indicates that Chilean seropositive RA patients display a genetic background that is different from that underlying RA susceptibility in other populations and suggests the existence of common, as well as distinct, genetic elements predisposing to seronegative and seropositive RA.     

The Application of Beta-Tricalcium Phosphate in Implant Dentistry: A Systematic Evaluation of Clinical Studies

The demand for synthetic graft materials in implant dentistry is rising. This systematic review aims to evaluate the survival rate of dental implants placed simultaneously with bone regeneration procedures using the material β-tricalcium phosphate, one of the most promising synthetic graft materials. The electronic search was conducted in PubMed, Scielo, and the Cochrane Central Register of Controlled Trials. Five randomized clinical trials, one non-randomized controlled clinical trial and four observational studies without control group were include. Implant survival rate and other clinical, radiographic, and histological parameters did not differ from those of implants placed simultaneously with another type of graft material, or placed in blood clots or natural alveolar ridges. Based on the available literature, β-tricalcium phosphate seems to be a promising graft material in implant dentistry. Nevertheless, more randomized clinical trials, with long follow-up periods, preoperative and postoperative CBCT, and histological analysis, are necessary to assess its long-term behavior.     

Omega-3 Fatty Acid Intake during Pregnancy and Child Neuropsychological Development: A Multi-Centre Population-Based Birth Cohort Study in Spain

Background: There are few studies that look at the intake of all types of omega-3 polyunsaturated fatty acids (n-3 PUFAs) during the different stages of pregnancy along with a long-term neuropsychological follow-up of the child. This study aims to explore the association between maternal n-3 PUFA intake during two periods of pregnancy and the child’s neuropsychological scores at different ages. Methods: Prospective data were obtained for 2644 pregnant women recruited between 2004 and 2008 in population-based birth cohorts in Spain. Maternal n-3 PUFA intake during the first and third trimester of pregnancy was estimated using validated food frequency questionnaires. Child neuropsychological functions were assessed using Bayley Scales of Infant Development version one (BSID) at 1 year old, the McCarthy Scale of Children’s Abilities (MSCA) at 4 years old, and the Attention Network Test (ANT) at 7 years old. Data were analysed using multivariate linear regression models and adjusted for potential covariates, such as maternal social class, education, cohort location, alcohol consumption, smoking, breastfeeding duration, and energy intake. Results: Compared to participants in the lowest quartile (<1.262 g/day) of n-3 PUFA consumption during the first trimester, those in the highest quartile (>1.657 g/day) had a 2.26 points (95% confidence interval (CI): 0.41, 4.11) higher MSCA general cognitive score, a 2.48 points (95% CI: 0.53, 4.43) higher MSCA verbal score, and a 2.06 points (95% CI: 0.166, 3.95) higher MSCA executive function score, and a 11.52 milliseconds (95% CI: −22.95, −0.09) lower ANT hit reaction time standard error. In the third pregnancy trimester, the associations were weaker. Conclusions: Positive associations between n-3 PUFA intake during early pregnancy and child neuropsychological functions at 4 and 7 years of age were found, and further clinical research is needed to confirm these findings.