Birth weight and blood lipid levels in Spanish adolescents: Influence of selected APOE, APOC3 and PPARgamma2 gene polymorphisms. The AVENA Study

Background There is increasing evidence indicating that genes involved in certain metabolic processes of cardiovascular diseases may be of particular influence in people with low body weight at birth. We examined whether the apolipoprotein (APO) E, APOC3 and the peroxisome proliferator-activated receptor-γ-2 (PPARγ2) polymorphisms influence the association between low birth weight and blood lipid levels in healthy adolescents aged 13–18.5 years. Methods A cross-sectional study of 502 Spanish adolescents born at term was conducted. Total (TC) and high density lipoprotein cholesterol (HDLc), triglycerides (TG), apolipoprotein (apo) A and B, and lipoprotein(a) [Lp(a)] were measured. Low density lipoprotein cholesterol (LDLc), TC-HDLc, TC/HDLc and apoB/apoA were calculated. Results Low birth weight was associated with higher levels of TC, LDLc, apoB, Lp(a), TC-HDLc, TC/HDLc and apoB/apoA in males with the APOE ε3ε4 genotype, whereas in females, it was associated with lower HDLc and higher TG levels. In males with the APOC3 S1/S2 genotype, low birth weight was associated with lower apoA and higher Lp(a), yet this association was not observed in females. There were no associations between low birth weight and blood lipids in any of the PPARγ2 genotypes. Conclusion The results indicate that low birth weight has a deleterious influence on lipid profile particularly in adolescents with the APOE ε3/ε4 genotype. These findings suggest that intrauterine environment interact with the genetic background affecting the lipid profile in later life.The AVENA study was supported by the Spanish Ministry of Health Instituto de Salud Carlos III (FIS PI021830), the Spanish Ministry of Health, FEDER-FSE funds FIS n° 00/0015, CSD grants 05/UPB32/0, 109/UPB31/03 and 13/UPB20/04, the Spanish Ministry of Education (AP-2004-2745; EX-2007-1124), scholarships from Panrico S.A., Madaus S.A. and Procter and Gamble S.A

Preventive and curative effect of melatonin on mammary carcinogenesis induced by dimethylbenz[a]anthracene in the female Sprague–Dawley rat

INTRODUCTION: It has been well documented that the pineal hormone, melatonin, which plays a major role in the control of reproduction in mammals, also plays a role in the incidence and growth of breast and mammary cancer. The curative effect of melatonin on the growth of dimethylbenz [a]anthracene-induced (DMBA-induced) mammary adenocarcinoma (ADK) has been previously well documented in the female Sprague–Dawley rat. However, the preventive effect of melatonin in limiting the frequency of cancer initiation has not been well documented. METHODS: The aim of this study was to compare the potency of melatonin to limit the frequency of mammary cancer initiation with its potency to inhibit tumor progression once initiation, at 55 days of age, was achieved. The present study compared the effect of preventive treatment with melatonin (10 mg/kg daily) administered for only 15 days before the administration of DMBA with the effect of long-term (6-month) curative treatment with the same dose of melatonin starting the day after DMBA administration. The rats were followed up for a year after the administration of the DMBA. RESULTS: The results clearly showed almost identical preventive and curative effects of melatonin on the growth of DMBA-induced mammary ADK. Many hypotheses have been proposed to explain the inhibitory effects of melatonin. However, the mechanisms responsible for its strong preventive effect are still a matter of debate. At least, it can be envisaged that the artificial amplification of the intensity of the circadian rhythm of melatonin could markedly reduce the DNA damage provoked by DMBA and therefore the frequency of cancer initiation. CONCLUSION: In view of the present results, obtained in the female Sprague–Dawley rat, it can be envisaged that the long-term inhibition of mammary ADK promotion by a brief, preventive treatment with melatonin could also reduce the risk of breast cancer induced in women by unidentified environmental factors

Estrogen and progesterone receptor levels in nonneoplastic breast epithelium of breast cancer cases versus benign breast biopsy controls

<p>Abstract</p> <p>Background</p> <p>Previous studies and biological mechanisms of carcinogenesis suggest that the steroid receptor content of benign breast epithelium may be related to breast cancer risk. The objective in this study was to compare the levels of estrogen receptor-α (ER) and progesterone receptor (PR) in nonneoplastic breast epithelium between breast cancer cases and biopsy controls.</p> <p>Methods</p> <p>Between 1995 and 1997 at two sites (Women's College Hospital in Toronto and Kingston General Hospital), 667 women who were scheduled for diagnostic excisional breast biopsies completed a questionnaire providing personal information and agreed to allow analysis of routinely resected tissue. Histological slides with nonneoplastic epithelium were available for 101 cancer cases and 200 biopsy controls in Toronto and for 105 cancer cases and 119 controls in Kingston. Nonneoplastic epithelium was examined with immunohistochemical assays to determine the percent of epithelial cells staining for ER and PR. Unconditional logistic regression was used to calculate odds ratios (OR) stratified by study site.</p> <p>Results</p> <p>The ER content of nonneoplastic tissue was higher in cases than biopsy controls in unadjusted analyses; after adjustment for age, however, a weak association remained in only one of the study sites. After adjustment for age, the PR content of nonneoplastic tissue was slightly lower in breast cancer cases than controls in one study site. Furthermore, this inverse association was confined to women with PR negative breast cancer in comparison to the controls. No interaction between ER and PR content of nonneoplastic tissue was observed in relation to the odds of having breast cancer.</p> <p>Conclusion</p> <p>The results of this study are consistent with only a slight indication of increased ER levels in nonneoplastic tissue in breast cancer cases relative to controls. This study contributes to the understanding of breast cancer by examining both ER and PR in nonneoplastic tissue. Limitations remain, however, such as the necessity of using as controls women with benign breast changes, difficulties in selecting the appropriate tissue for analysis, and tissue sampling concurrent to diagnosis.</p

Altered sense of Agency in children with spastic cerebral palsy

<p>Abstract</p> <p>Background</p> <p>Children diagnosed with spastic Cerebral Palsy (CP) often show perceptual and cognitive problems, which may contribute to their functional deficit. Here we investigated if altered ability to determine whether an observed movement is performed by themselves (sense of agency) contributes to the motor deficit in children with CP.</p> <p>Methods</p> <p>Three groups; ₁₎CP children, ₂₎healthy peers, and ₃₎healthy adults produced straight drawing movements on a pen-tablet which was not visible for the subjects. The produced movement was presented as a virtual moving object on a computer screen. Subjects had to evaluate after each trial whether the movement of the object on the computer screen was generated by themselves or by a computer program which randomly manipulated the visual feedback by angling the trajectories 0, 5, 10, 15, 20 degrees away from target.</p> <p>Results</p> <p>Healthy adults executed the movements in 310 seconds, whereas healthy children and especially CP children were significantly slower (p < 0.002) (on average 456 seconds and 543 seconds respectively). There was also a statistical difference between the healthy and age matched CP children (p = 0.037). When the trajectory of the object generated by the computer corresponded to the subject's own movements all three groups reported that they were responsible for the movement of the object. When the trajectory of the object deviated by more than 10 degrees from target, healthy adults and children more frequently than CP children reported that the computer was responsible for the movement of the object. CP children consequently also attempted to compensate more frequently from the perturbation generated by the computer.</p> <p>Conclusions</p> <p>We conclude that CP children have a reduced ability to determine whether movement of a virtual moving object is caused by themselves or an external source. We suggest that this may be related to a poor integration of their intention of movement with visual and proprioceptive information about the performed movement and that altered sense of agency may be an important functional problem in children with CP.</p

Access to emergency department for acute events and identification of sickle cell disease in refugees.

Throughout the last decade, thousands of refugees arrived on a daily basis on the Mediterranean coast of Southern-European countries. As this influx is not expected to slow down, developing national and European strategies is required to ensure appropriate and accessible health care to these vulnerable populations.1,2 The vast majority of these migrants come from areas in which sickle cell disease (SCD) and other hemoglobinopathies are highly prevalent. Limited data are available on the burden of these disorders in populations of refugees. Here, we present two pieces of evidence supporting the need for specific strategies for the early identification of SCD in refugees. First, we carried out a retrospective study of data collected during the period 2014-2017 across 13 Italian reference centers for SCD and hemoglobinopathies. The primary outcome of this study was to identify events associated with the new diagnosis of SCD in refugees and the secondary outcome was to evaluate the impact of hemoglobinopathies in refugees coming from endemic areas. The descriptive analysis of variables was performed with counts, percentages, mean and standard deviation (SD) or median and interquartile range (IQR: 25th - 75th percentile). Then, we discuss the results of a pilot study which screened all refugees seen in a single second-level refugee center during October 2017, using one of the new rapid point of care screening devices (SickleSCAN\uae BioMedomics, inc.). The aim was to fast-track the care of individuals with SCD and the collection of relevant demographic data.3-5 The results were then validated by HPLC, the standard gold-standard screening method.3-

Transfusional approach in multi-ethnic Sickle Cell patients: real-world practice data from a Multicenter survey in Italy

Sickle cell disease (SCD) is a worldwide distributed hereditary red cell disorder characterized by recurrent acute vaso-occlusive crises (VOCs and anemia). Gold standard treatments are hydroxycarbamide (HC) and/or different red blood cell (RBC) transfusion regimens to limit disease progression. Here, we report a retrospective study on 1,579 SCD patients (median age 23 years; 802 males/777 females), referring to 34 comprehensive Italian centers for hemoglobinopathies. Although we observed a similar proportion of Caucasian (47.9%) and African (48.7%) patients, Italian SCD patients clustered into two distinct overall groups: children of African descent and adults of Caucasian descent. We found a subset of SCD patients requiring more intensive therapy with a combination of HC plus chronic transfusion regimen, due to partial failure of HC treatment alone in preventing or reducing sickle cell-related acute manifestations. Notably, we observed a higher use of acute transfusion approaches for SCD patients of African descent when compared to Caucasian subjects. This might be related to (i) age of starting HC treatment; (ii) patients' low social status; (iii) patients' limited access to family practitioners; or (iv) discrimination. In our cohort, alloimmunization was documented in 135 patients (8.5%) and was more common in Caucasians (10.3%) than in Africans (6.6%). Alloimmunization was similar in male and female and more frequent in adults than in children. Our study reinforces the importance of donor-recipient exact matching for ABO, Rhesus, and Kell antigen systems for RBC compatibility as a winning strategy to avoid or limit alloimmunization events that negatively impact the clinical management of SCD-related severe complications

Transcriptome of iPSC-derived neuronal cells reveals a module of co-expressed genes consistently associated with autism spectrum disorder

Evaluation of expression profile in autism spectrum disorder (ASD) patients is an important approach to understand possible similar functional consequences that may underlie disease pathophysiology regardless of its genetic heterogeneity. Induced pluripotent stem cell (iPSC)-derived neuronal models have been useful to explore this question, but larger cohorts and different ASD endophenotypes still need to be investigated. Moreover, whether changes seen in this in vitro model reflect previous findings in ASD postmortem brains and how consistent they are across the studies remain underexplored questions. We examined the transcriptome of iPSC-derived neuronal cells from a normocephalic ASD cohort composed mostly of high-functioning individuals and from non-ASD individuals. ASD patients presented expression dysregulation of a module of co-expressed genes involved in protein synthesis in neuronal progenitor cells (NPC), and a module of genes related to synapse/neurotransmission and a module related to translation in neurons. Proteomic analysis in NPC revealed potential molecular links between the modules dysregulated in NPC and in neurons. Remarkably, the comparison of our results to a series of transcriptome studies revealed that the module related to synapse has been consistently found as upregulated in iPSC-derived neurons-which has an expression profile more closely related to fetal brain-while downregulated in postmortem brain tissue, indicating a reliable association of this network to the disease and suggesting that its dysregulation might occur in different directions across development in ASD individuals. Therefore, the expression pattern of this network might be used as biomarker for ASD and should be experimentally explored as a therapeutic target

High-Resolution Functional Mapping of the Venezuelan Equine Encephalitis Virus Genome by Insertional Mutagenesis and Massively Parallel Sequencing

We have developed a high-resolution genomic mapping technique that combines transposon-mediated insertional mutagenesis with either capillary electrophoresis or massively parallel sequencing to identify functionally important regions of the Venezuelan equine encephalitis virus (VEEV) genome. We initially used a capillary electrophoresis method to gain insight into the role of the VEEV nonstructural protein 3 (nsP3) in viral replication. We identified several regions in nsP3 that are intolerant to small (15 bp) insertions, and thus are presumably functionally important. We also identified nine separate regions in nsP3 that will tolerate small insertions at low temperatures (30°C), but not at higher temperatures (37°C, and 40°C). Because we found this method to be extremely effective at identifying temperature sensitive (ts) mutations, but limited by capillary electrophoresis capacity, we replaced the capillary electrophoresis with massively parallel sequencing and used the improved method to generate a functional map of the entire VEEV genome. We identified several hundred potential ts mutations throughout the genome and we validated several of the mutations in nsP2, nsP3, E3, E2, E1 and capsid using single-cycle growth curve experiments with virus generated through reverse genetics. We further demonstrated that two of the nsP3 ts mutants were attenuated for virulence in mice but could elicit protective immunity against challenge with wild-type VEEV. The recombinant ts mutants will be valuable tools for further studies of VEEV replication and virulence. Moreover, the method that we developed is applicable for generating such tools for any virus with a robust reverse genetics system

Effects of acute treatment with a tryptophan-rich protein hydrolysate on plasma amino acids, mood and emotional functioning in older women

RATIONALE: Effective functioning of the neurotransmitter serotonin is important for optimal cognitive and emotional function. Dietary supplements able to increase availability to the brain of the precursor amino acid, tryptophan (TRP), and thereby enhance serotonin synthesis, can have measurable impact on these psychological processes. OBJECTIVES: This study involves a randomised controlled trial of a TRP-rich egg-white protein hydrolysate (DSM Nutritional Products Ltd., Switzerland) on plasma amino acids, cognition, mood and emotional processing in older women. METHODS: Following a baseline test day without treatment, 60 healthy women aged 45–65 years received drinks containing either 2 or 4 g of TRP-rich protein hydrolysate product or 3.11 g casein hydrolysate as a control. One hour later, they undertook a 2-h battery of cognitive and emotional tests. RESULTS: The TRP-rich protein hydrolysate produced the expected dose-dependent increase in the ratio of plasma TRP to competing large neutral amino acids. TRP-rich protein hydrolysate (2 g only) prevented both the decline in wellbeing and increase in fatigue seen over the test session in the control group. This treatment dose resulted in a significant shift in emotional processing towards positive words and reduced negative bias in assessing negative facial expressions. Effects on cognition were small and not statistically reliable and are not reported here. However, there was no evidence for any adverse effects. CONCLUSIONS: Consumption of a low dose of TRP-rich protein hydrolysate may have beneficial effects on emotional function that could promote feelings of wellbeing, possibly conferring resistance to deterioration in mood in healthy subjects or depressive episodes