Contributors to disease‐specific health knowledge in adults with congenital heart disease: A correlational study

Objective: Growth in the adults with congenital heart disease (ACHD) population represents a challenge to the health care infrastructure. As patients with chronic disease are increasingly held accountable for their own care, contributors to disease‐ specific health knowledge, which are known to correlate with patients’ participation in care, merit investigation to design patient‐focused interventions.
Design: We conducted a single‐site, cross‐sectional study of ACHD patients. Investigators retrospectively gathered clinical data as well as psychometric and health status assessments completed at the time of enrollment.
Outcome Measures: We investigated the impact of clinical and psychological varia‐ bles on Leuven Knowledge Questionnaire for Congenital Heart Diseases health knowledge composite scores (HKCS). Variables with significant associations were considered in a stepwise multivariable regression model to determine which combi‐ nation of variables jointly explained variability in HKCS.
Results: Overall HKCS was associated with the number of prior cardiac surgeries (r = 0.273; 95% CI: 0.050‐0.467; P = .016), perceived stress (r = 0.260; 95% CI: 0.033‐0.458; P = .024), SF‐36 emotional well‐being (r = −0.251; 95% CI: −0.451, −0.024; P = .030), history of noncardiac surgery (P = .037), cirrhosis (P = .048), and presence of implantable cardioverter‐defibrillator (P = .028). On multivariable mod‐ eling, only the number of cardiac surgeries was found to correlate with HKCS.
Conclusions: While univariate correlations were found between HCKS and several other clinical and psychological variables, only number of prior cardiac surgeries inde‐ pendently correlated with disease‐specific health knowledge in ACHD patients. These results suggest that clinical and psychological variables are not impediments to disease‐specific health knowledge.     

Smaller hippocampal subfield volumes predict verbal associative memory in pediatric brain tumor survivors

The developing hippocampus is highly sensitive to chemotherapy and cranial radiation treatments for pediatric cancers, yet little is known about the effects that cancer treatents have on specific hippocampal subfields. Here, we examined hippocampal subfield volumes in 29 pediatric brain tumor survivors treated with cranial radiation and chemotherapy, and 30 healthy developing children and adolescents. We also examined associations between hippocampal subfield volumes and short‐term verbal memory. Hippocampal subfields (Cornus Ammonis (CA) 1, CA2‐3, dentate gyrus (DG)‐CA4, stratum radiatum—lacunosum—moleculare, and subiculum) were segmented using the Multiple Automatically Generated Templates for Different Brains automated segmentation algorithm. Neuropsychological assessment of short‐term verbal associative memory was performed in a subset of brain tumor survivors (N = 11) and typically developing children (N = 16), using the Children's Memory Scale or Wechsler's Memory Scale—third edition. Repeated measures analysis of variance showed that pediatric brain tumor survivors had significantly smaller DG‐CA4, CA1, CA2‐3, and stratum radiatum‐lacunosum‐moleculare volumes compared with typically developing children. Verbal memory performance was positively related to DG‐CA4, CA1, and stratum radiatum‐lacunosum‐moleculare volumes in pediatric brain tumor survivors. Unlike the brain tumor survivors, there were no associations between subfield volumes and memory in typically developing children and adolescents. These data suggest that specific subfields of the hippocampus may be vulnerable to brain cancer treatments, and may contribute to impaired episodic memory following brain cancer treatment in childhood.     

Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices

Soluble amyloid beta (Aβ) oligomers are widely accepted to be neurotoxic and lead to the memory loss and neuronal death observed in Alzheimer’s disease (AD). Ample evidence suggests that impairment in glutamatergic signalling is associated with AD pathology. In particular, Aβ_1-42 is thought to affect N-methyl-d-aspartate (NMDA) receptor function and abolish the induction of long-term potentiation (LTP), which is regarded to be a phenomenon relevant to memory formation. The involvement of glutamatergic signalling in the pathology of AD is underscored by the therapeutic success of memantine, an uncompetitive NMDA receptor antagonist, used to treat patients with moderate to severe AD. In this study we show that Aβ_1-42 oligomers applied to acute murine hippocampal slices prevented, in a concentration-dependent manner, the development of CA1-LTP after tetanic stimulation of the Schaffer collaterals with a half maximal inhibitory concentration of around 2 nM (before oligomerization). The highest concentration of Aβ_1-42 oligomers (50 nM before oligomerization) completely blocked LTP (105 ± 1% potentiation versus 141 ± 3% in control) whereas scrambled Aβ_1-42 (50 nM) was without effect (144 ± 10% potentiation).Pre-incubation with memantine (1 μM) restored LTP in the presence of Aβ_1-42 (50 nM; 135 ± 5% potentiation). NMDA receptors containing the NR2B subunit have been proposed to play a particularly important role in excitotoxicity, functioning as extracellular “death receptors”. The metabotropic glutamate receptor 5 (mGluR5) is mechanistically coupled to postsynaptic NMDA receptors. As such, allosteric sites on both receptors offer alternative means to modulate NMDA receptor function. We therefore tested low concentrations (each 300 nM) of allosteric antagonists of NR2B (Ro 25-6981, [R-(R∗,S∗)]-α-(4-Hydroxyphenyl)-β-methyl-4(phenylmethyl)-1-piperidine propanol hydrochloride) and mGluR5 receptors (MPEP, 2-methyl-6-(phenylethynyl)-pyridine). Both compounds restored LTP in the presence of Aβ_1-42 oligomers (50 nM, fEPSPs were potentiated to 129 ± 13% and 133 ± 7% respectively). Finally, we demonstrated that slices from mice heterozygous for NR2B receptor) in the forebrain are not susceptible to the toxic effects of Aβ_1-42 oligomers but express normal LTP (138 ± 6%). These experiments demonstrate that glutamate receptor antagonists delivered at concentrations which still allow physiological activities in vitro, are able to prevent Aβ_1-42 oligomer-induced synaptic toxicity and further support the glutamatergic system as a target for the development of improved symptomatic/neuroprotective treatments for AD.     

Genetic variation in the androgen estrogen conversion pathway in relation to breast cancer prognosticators

Genetic variation in the androgen-to-estrogen conversion pathway has been shown to be associated with risk of breast cancer and, in particular, with estrogen receptor (ER) positive tumours. We aimed at studying how the genetic alterations, which have been identified for risk, are associated with breast cancer prognosticators, with a prior hypothesis that, in general, hormone-related breast cancers have a better prognosis than non-hormone-related breast cancers. Association between tagging SNPs in genes involved in estrogen metabolism and patient’s lymph node status, tumour size and histological grade were estimated in a sample of 1569 Swedish breast cancer patients. Polymorphisms in CYP19A1, which have previously been linked to breast cancer risk, are shown to be associated with breast cancer prognosticators. The strongest association was observed for rs4646, with histological grade. The common allele of rs4646, which has been associated with increased breast cancer risk, was associated with low-histological grade and small tumour size (P = 0.001 and 0.015; 1-sided, respectively). We also found evidence that SNP rs7167936 is associated with histological grade and tumour size (P = 0.010 and 0.005; 1-sided, respectively). We show that rs4646 and rs7167936 are associated with histological grade even amongst only ER-positive tumours (P = 0.008 and 0.011; 1-sided, respectively). Our results provide new evidence that CYP19A1 is involved in both breast cancer risk and prognosis.     

A combined analysis of genome-wide association studies in breast cancer

In an attempt to identify common disease susceptibility alleles for breast cancer, we performed a combined analysis of three genome-wide association studies (GWAS), involving 2,702 women of European ancestry with invasive breast cancer and 5,726 controls. Tests for association were performed for 285,984 SNPs. Evidence for association with SNPs in genes in specific pathways was assessed using a permutation-based approach. We confirmed associations with loci reported by previous GWAS on 1p11.2, 2q35, 3p, 5p12, 8q24, 10q23.13, 14q24.1 and 16q. Six SNPs with the strongest signals of association with breast cancer, and which have not been reported previously, were typed in two further studies; however, none of the associations could be confirmed. Suggestive evidence for an excess of associations was found for genes involved in the regulation of actin cytoskeleton, glycan degradation, alpha-linolenic acid metabolism, circadian rhythm, hematopoietic cell lineage and drug metabolism. Androgen and oestrogen metabolism, a pathway previously found to be associated with the development of postmenopausal breast cancer, was marginally significant (P = 0.051 [unadjusted]). These results suggest that further analysis of SNPs in these pathways may identify associations that would be difficult to detect through agnostic single SNP analyses. More effort focused in these aspects of oncology can potentially open up promising avenues for the understanding of breast cancer and its prevention.     

Development of systemic lupus erythematosus in a patient with hypoparathyroidism: a case report and review of the literature

Systemic lupus erythematosus (SLE) is an autoimmune disease in which organs undergo damage. Hypoparathyroidism is a rare disease, which presents in two forms: hereditary and acquired. Cases of hypoparathyroidism and SLE rarely co‐exist. Only six cases have been reported; five of them first presented with lupus and then hypoparathyroidism or simultaneously. We present here developing lupus disease in a woman who had idiopathic hypoparathyroidism. According to increasing data about the autoimmune origin of idiopathic hypoparathyroidism, these case reports suggest that there may be an autoimmune process linking these diseases.     

Isolation, structure elucidation, and biosynthesis of an unusual hydroxamic acid ester-containing siderophore from Actinosynnema mirum

In this study we report the isolation, structure elucidation, and biosynthesis of mirubactin (1), a siderophore containing an unprecedented chemical functionality in natural products, namely, an O-acyl hydroxamic acid ester. Mirubactin represents the first siderophore isolated from the genus Actinosynnema and the first natural product produced by Actinosynnema mirum whose biosynthetic gene cluster could be identified. Structure elucidation was accomplished through a combination of spectroscopic (NMR, IR, and UV/vis) and mass spectrometric methods and revealed the presence of an unusual ester bond between the δ-N-hydroxyl group of δ-N-formyl-δ-N-hydroxyornithine and a 2,3-dihydroxybenzoate moiety. Bioinformatic analysis of the A. mirum genome and subsequent biochemical characterization of the putative biosynthetic machinery identified the gene cluster responsible for mirubactin assembly. The proposed biosynthesis of mirubactin comprises the iterative use of a stand-alone carrier-protein-bound substrate, as well as an ester-bond-forming step catalyzed by a C-terminal condensation domain, thus revealing an interesting system for further biochemical studies to gain a deeper understanding of nonribosomal peptide synthetase-catalyzed siderophore biosynthesis.