Birth seasonality studies in a large Prader-Willi syndrome cohort.

Prader-Willi syndrome (PWS) is generally due to sporadic paternal deletions of the chromosome 15q11-q13 region followed by maternal disomy 15. Advanced maternal age is more commonly seen in those with maternal disomy 15. Environmental factors (e.g., drug use, occupational chemical exposure, infectious agents, and irradiation) could account for chromosome changes. Previous evidence of differences in male and female gametogenesis could suggest an environmental role in the causation of the paternal 15q11-q13 deletion seen in PWS. Certain occupations such as hydrocarbon-exposing occupations (e.g., landscaping, farming, and painting) and viral exposure (e.g., human coronavirus 229E causing upper respiratory infections in adults with an incorporation site in the human genome at chromosome 15q11) can be seasonal in nature and contribute to chromosome damage. To assess, we reviewed birth seasonality data in a large cohort of individuals with PWS recruited nationally (N = 355) but no significant differences were seen by month between those with the 15q11-q13 deletion compared with maternal disomy 15 when analyzing quarterly seasonal patterns. Although early evidence supported birth seasonality differences in PWS, a larger number of individuals in our recent study using advanced genetic testing methods did not find this observation

Early Diagnosis in Prader-Willi Syndrome Reduces Obesity and Associated Co-Morbidities.

Prader-Willi syndrome (PWS) is an imprinting genetic disorder characterized by lack of expression of genes on the paternal chromosome 15q11-q13 region. Growth hormone (GH) replacement positively influences stature and body composition in PWS. Our hypothesis was that early diagnosis delays onset of obesity in PWS. We studied 352 subjects with PWS, recruited from the NIH Rare Disease Clinical Research Network, to determine if age at diagnosis, ethnicity, gender, and PWS molecular class influenced the age they first become heavy, as determined by their primary care providers, and the age they first developed an increased appetite and began seeking food. The median ages that children with PWS became heavy were 10 years, 6 years and 4 years for age at diagnosis < 1 year, between 1 and 3 years, and greater than 3 years of age, respectively. The age of diagnosis and ethnicity were significant factors influencing when PWS children first became heavy (p < 0.01), however gender and the PWS molecular class had no influence. Early diagnosis delayed the onset of becoming heavy in individuals with PWS, permitting early GH and other treatment, thus reducing the risk of obesity-associated co-morbidities. Non-white individuals had an earlier onset of becoming heavy

Sulfonylurea derivatives and cancer, friend or foe?

Type 2 diabetes mellitus (T2DM) is associated with a higher risk of cancer and cancer-related mortality. Increased blood glucose and insulin levels in T2DM patients may be, at least in part, responsible for this effect. Indeed, lowering glucose and/or insulin levels pharmacologically appears to reduce cancer risk and progression, as has been demonstrated for the biguanide metformin in observational studies. Studies investigating the influence of sulfonylurea derivatives (SUs) on cancer risk have provided conflicting results, partly due to comparisons with metformin. Furthermore, little attention has been paid to within-class differences in systemic and off-target effects of the SUs. The aim of this systematic review is to discuss the available preclinical and clinical evidence on how the different SUs influence cancer development and risk. Databases including PubMed, Cochrane, Database of Abstracts on Reviews and Effectiveness, and trial registries were systematically searched for available clinical and preclinical evidence on within-class differences of SUs and cancer risk. The overall preclinical and clinical evidence suggest that the influence of SUs on cancer risk in T2DM patients differs between the various SUs. Potential mechanisms include differing affinities for the sulfonylurea receptors and thus differential systemic insulin exposure and off-target anti-cancer effects mediated for example through potassium transporters and drug export pumps. Preclinical evidence supports potential anti-cancer effects of SUs, which are of interest for further studies and potentially repurposing of SUs. At this time, the evidence on differences in cancer risk between SUs is not strong enough to guide clinical decision making

Arylmethylamino steroids as antiparasitic agents

In search of antiparasitic agents, we here identify arylmethylamino steroids as potent compounds and characterize more than 60 derivatives. The lead compound 1o is fast acting and highly active against intraerythrocytic stages of chloroquine-sensitive and resistant Plasmodium falciparum parasites (IC50 1–5?nM) as well as against gametocytes. In P. berghei-infected mice, oral administration of 1o drastically reduces parasitaemia and cures the animals. Furthermore, 1o efficiently blocks parasite transmission from mice to mosquitoes. The steroid compounds show low cytotoxicity in mammalian cells and do not induce acute toxicity symptoms in mice. Moreover, 1o has a remarkable activity against the blood-feeding trematode parasite Schistosoma mansoni. The steroid and the hydroxyarylmethylamino moieties are essential for antimalarial activity supporting a chelate-based quinone methide mechanism involving metal or haem bioactivation. This study identifies chemical scaffolds that are rapidly internalized into blood-feeding parasites

Multicentre study of maternal and neonatal outcomes in individuals with Prader-Willi syndrome.

INTRODUCTION:Prader-Willi syndrome (PWS) is a complex genetic disorder associated with three different genetic subtypes: deletion of the paternal copy of 15q11-q13, maternal UPD for chromosome 15 and imprinting defect. Patients are typically diagnosed because of neonatal hypotonia, dysmorphism and feeding difficulties; however, data on the prenatal features of PWS are limited. OBJECTIVE:The aim of the study was to identify and compare frequencies of prenatal and neonatal clinical features of PWS among the three genetic subtypes. METHODS:Data from 355 patients with PWS from the Rare Diseases Clinical Research Network PWS registry were used to analyse multiple maternal and neonatal factors collected during an 8-year multisite study. RESULTS:Among our cohort of 355 patients with PWS (61% deletion, 36% UPD and 3% imprinting defect) 54% were born by caesarean section, 26% were born prematurely and 34% with a low birth weight (frequencies 32%, 9.6% and 8.1%, respectively, in the general population). Fetal movements were reported as decreased in 72%. All babies were hypotonic, and 99% had feeding difficulties. Low Apgar scores (<7) were noted in 17.7% and 5.6% of patients, respectively, compared with 1% and 1.4%, respectively, in the general population. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (p=0.01 and <0.001, respectively). CONCLUSION:We found a higher rate of perinatal complications in PWS syndrome compared with the general population. No significant differences in the genetic subtypes were noted except for a higher maternal age and pre-pregnancy weight in the UPD subgroup

The effect of enteral bolus feeding on regional intestinal oxygen saturation in preterm infants is age-dependent:a longitudinal observational study

Background The factors that determine the effect of enteral feeding on intestinal perfusion after preterm birth remain largely unknown. We aimed to determine the effect of enteral feeding on intestinal oxygen saturation (r(int)SO(2)) in preterm infants and evaluated whether this effect depended on postnatal age (PNA), postmenstrual age (PMA), and/or feeding volumes. We also evaluated whether changes in postprandial r(int)SO(2) affected cerebral oxygen saturation (r(c)SO(2)). Methods In a longitudinal observational pilot study using near-infrared spectroscopy we measured r(int)SO(2) and r(c)SO(2) continuously for two hours on postnatal Days 2 to 5, 8, 15, 22, 29, and 36. We compared preprandial with postprandial values over time using multi-level analyses. To assess the effect of PNA, PMA, and feeding volumes, we performed Wilcoxon signed-rank tests or logistic regression analyses. To evaluate the effect on r(c)SO(2), we also used logistic regression analyses. Results We included 29 infants: median (range) gestational age 28.1 weeks (25.1-30.7) and birth weight 1025 g (580-1495). On Day 5, r(int)SO(2) values decreased postprandially: mean (SE) 44% (10) versus 35% (7), P = .01. On Day 29, r(int)SO(2) values increased: 44% (11) versus 54% (7), P = .01. Infants with a PMA >= 32 weeks showed a r(int)SO(2) increase after feeding (37% versus 51%, P = .04) whereas infants with a PMA = 32 weeks when greater volumes of enteral feeding are tolerated. We speculate that at young gestational and postmenstrual ages preterm infants are still unable to increase intestinal oxygen saturation after feeding, which might be essential to meet metabolic demands. Trial registration: For this prospective longitudinal pilot study we derived patients from a larger observational cohort study: CALIFORNIA-Trial, Dutch Trial Registry NTR4153

A novel mutation causing mild, atypical fumarylacetoacetase deficiency (Tyrosinemia type I): a case report

A male patient, born to unrelated Belgian parents, presented at 4 months with epistaxis, haematemesis and haematochezia. On physical examination he presented petechiae and haematomas, and a slightly enlarged liver. Serum transaminases were elevated to 5-10 times upper limit of normal, alkaline phosphatases were 1685 U/L (<720), total bilirubin was 2.53 mg/dl (<1.0), ammonaemia 69 μM (<32), prothrombin time less than 10%, thromboplastin time >180 s (<60) and alpha-fetoprotein 29723 μg/L (<186). Plasma tyrosine (651 μM) and methionine (1032 μM) were strongly increased. In urine, tyrosine metabolites and 4-oxo-6-hydroxyheptanoic acid were increased, but succinylacetone and succinylacetoacetate - pathognomonic for tyrosinemia type I - were repeatedly undetectable. Delta-aminolevulinic acid was normal, which is consistent with the absence of succinylacetone. Abdominal ultrasound and brain CT were normal

Corrigendum: Combining Literature Review With a Ground Truth Approach for Diagnosing Huntington's Disease Phenocopy.

[This corrects the article DOI: 10.3389/fneur.2022.817753.]

Modeling of Cisplatin-Induced Signaling Dynamics in Triple-Negative Breast Cancer Cells Reveals Mediators of Sensitivity

Triple-negative breast cancers (TNBCs) display great diversity in cisplatin sensitivity that cannot be explained solely by cancer-associated DNA repair defects. Differential activation of the DNA damage response (DDR) to cisplatin has been proposed to underlie the observed differential sensitivity, but it has not been investigated systematically. Systems-level analysis-using quantitative time-resolved signaling data and phenotypic responses, in combination with mathematical modeling-identifies that the activation status of cell-cycle checkpoints determines cisplatin sensitivity in TNBC cell lines. Specifically, inactivation of the cell-cycle checkpoint regulator MK2 or G3BP2 sensitizes cisplatin-resistant TNBC cell lines to cisplatin. Dynamic signaling data of five cell cycle-related signals predicts cisplatin sensitivity of TNBC cell lines. We provide a time-resolved map of cisplatin-induced signaling that uncovers determinants of chemo-sensitivity, underscores the impact of cell-cycle checkpoints on cisplatin sensitivity, and offers starting points to optimize treatment efficacy