Snyder-Robinson Syndrome (SRS) is an X-linked intellectual disability disorder also characterized by osteoporosis, scoliosis, and dysmorphic facial features. It is caused by mutations in SMS, a ...ubiquitously expressed gene encoding the polyamine biosynthetic enzyme spermine synthase. We hypothesized that the tissue specificity of SRS arises from differential sensitivity to spermidine toxicity or spermine deficiency.
We performed detailed clinical, endocrine, histopathologic, and morphometric studies on two affected brothers with a spermine synthase loss of function mutation (NM_004595.4:c.443A > G, p.Gln148Arg). We also measured spermine and spermidine levels in cultured human bone marrow stromal cells (hBMSCs) and fibroblasts using the Biochrom 30 polyamine protocol and assessed the osteogenic potential of hBMSCs.
In addition to the known tissue-specific features of SRS, the propositi manifested retinal pigmentary changes, recurrent episodes of hyper- and hypoglycemia, nephrocalcinosis, renal cysts, and frequent respiratory infections. Bone histopathology and morphometry identified a profound depletion of osteoblasts and osteoclasts, absence of a trabecular meshwork, a low bone volume and a thin cortex. Comparison of cultured fibroblasts from affected and unaffected individuals showed relatively small changes in polyamine content, whereas comparison of cultured osteoblasts identified marked differences in spermidine and spermine content. Osteogenic differentiation of the SRS-derived hBMSCs identified a severe deficiency of calcium phosphate mineralization.
Our findings support the hypothesis that cell specific alterations in polyamine metabolism contribute to the tissue specificity of SRS features, and that the low bone density arises from a failure of mineralization.
Parents of children with disorders of sex development (DSD) report significant psychological distress, including posttraumatic stress symptoms (PTSS), with mothers consistently reporting higher rates ...of psychological distress than fathers. However, psychological factors contributing to PTSS in both parents are not well understood. The present study sought to fill this gap in knowledge by examining PTSS and illness uncertainty, a known predictor of psychological distress, in parents of children recently diagnosed with DSD. Participants were 52 mothers (
M
age
= 32.55 years,
SD
= 5.08) and 41 fathers (
M
age
= 35.53 years,
SD
= 6.78) of 53 infants (
M
age
= 9.09 months,
SD
= 6.19) with DSD and associated atypical genital development. Participants were recruited as part of a larger, multisite study assessing parents’ psychosocial response to their child’s diagnosis of DSD. Parents completed measures of illness uncertainty and PTSS. Mothers reported significantly greater levels of PTSS, but not illness uncertainty, than fathers, and were more likely than fathers to report clinical levels of PTSS (21.2% compared to 7.3%). Hierarchical regression revealed that parent sex, undiagnosed or unclassified DSD status, and illness uncertainty were each associated with PTSS. The overall model accounted for 23.5% of the variance associated with PTSS. Interventions targeting illness uncertainty may be beneficial for parents of children with newly diagnosed DSD.
To describe the baseline participant characteristics in the ASPREE-AMD study, investigating the effect of aspirin on AMD incidence and progression.
Australian participants from the ASPirin in ...Reducing Events in the Elderly (ASPREE) trial, randomized to 100 mg aspirin daily or placebo, had non-mydriatic, digital color fundus images graded according to the Beckman AMD classification. Associations with AMD were determined for baseline characteristics and genetic risk variants.
ASPREE-AMD sub-study enrolled 4993 participants with gradable macular images. Median age was 73.4 years (IQR, 71.5, 76.6), 52% were female, 10% had diabetes mellitus, 73% had hypertension, and 44% were former/current smokers. Early, intermediate and late AMD (detected in 20.6%, 16.1%, 1.1%, respectively), significantly associated with age, were also associated with increasing HDL levels: OR = 1.52 (95%CI, 1.26, 1.84), OR = 1.43 (1.17, 1.77) and OR = 1.96 (1.02, 3.76), respectively. Female sex was associated with early OR = 1.37 (1.16, 1.62), and intermediate OR = 1.35 (1.12, 1.63) AMD, as was previous regular use of aspirin, with OR = 1.46 (1.11, 1.92) and OR = 1.37 (1.01, 1.85), respectively. Current smoking had increased odds for late AMD, OR = 4.02 (1.42, 11.36). Genetic risk variant rs3750846 (ARMS2/HTRA1) was associated with each AMD stage (p < 0.001), risk variants rs570618 and rs10922109 (CFH) with intermediate and late AMD (p < 0.001), and rare variant rs147859257 (C3) with late AMD (p < 0.001). The randomized groups were well balanced for all analyzed AMD risk factors.
Observed associations are typical of AMD. The ASPREE-AMD clinical trial provides a unique opportunity to determine the risks and benefits of low-dose aspirin for AMD incidence and progression in elderly population.
Australian New Zealand Clinical Trial Registry: ACTRN 12613000755730.
Abstract
Background
When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient’s phenotypes. Typically, this ...is done through annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance.
Methods
We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network.
Results
We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20.
Conclusions
We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and ...make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
Effect of the dialysis membrane on mortality of chronic hemodialysis patients. Mortality of prevalent chronic hemodialysis patients remains high. The potential effect of the dialysis membrane on this ...mortality has not been previously investigated in a large population of chronic hemodialysis patients. Using data from the United States Renal Data System (USRDS), we analyzed a random sample of 6,536 patients receiving hemodialysis on December 31, 1990. The study design was a historical prospective study. By limiting the study to patients dialyzed for at least one year with bicarbonate dialysate, in whom the dose of dialysis could be calculated, and in whom dialysis membrane and co-existing morbidities were defined, the sample size was reduced to 2,410 patients. A Cox proportional hazards model was used to estimate relative mortality risk. The types of dialysis membranes used were broadly classified into three categories: unsubstituted cellulose, modified cellulose (generally cellulose membranes that have been modified by substitutions of some or most of their hydroxyl moieties) and synthetic membranes that are not cellulose-based. The results of the study suggest that after adjusting for the dose of dialysis and the presence of co-morbid factors, the relative risk of mortality of patients dialyzed with modified cellulose or synthetic membranes was at least 25% less than that of patients treated with unsubstituted cellulose membranes (P < 0.001). To account for the possibility that these differences were due to regional practice patterns, we further stratified the data for nine different regions. There was still a 20% difference in relative risk of mortality between membrane groups with the mortality statistically significantly less in patients treated with synthetic membranes (P < 0.045) compared to patients dialyzed with unsubstituted cellulose membranes. The results of this study suggest that the dialysis membrane plays an important role in the outcome of chronic hemodialysis patients. However, more definitive studies are needed before a cause and effect relationship can be proven.
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The antioxidant natural product sulforaphane (SFN) is an oil with poor aqueous and thermal stability. Recent work with SFN has sought to optimize methods of formulation for oral and ...topical administration. Herein we report the design of new analogs of SFN with the goal of improving stability and drug-like properties. Lead compounds were selected based on potency in a cellular screen and physicochemical properties. Among these, 12 had good aqueous solubility, permeability and long-term solid-state stability at 23 °C. Compound 12 also displayed comparable or better efficacy in cellular assays relative to SFN and had in vivo activity in a mouse cigarette smoke challenge model of acute oxidative stress.
The "diagnostic odyssey" describes the process those with undiagnosed conditions undergo to identify a diagnosis. Throughout this process, families of children with undiagnosed conditions have ...multiple opportunities to decide whether to continue or stop their search for a diagnosis and accept the lack of a diagnostic label. Previous studies identified factors motivating a family to begin searching, but there is limited information about the decision-making process in a prolonged search and how the affected child impacts a family's decision. This study aimed to understand how families of children with undiagnosed diseases decide whether to continue to pursue a diagnosis after standard clinical testing has failed. Parents who applied to the Undiagnosed Disease Network (UDN) at the National Institutes of Health (NIH) were recruited to participate in semi-structured interviews. The 2015 Supportive Care Needs model by Pelenstov, which defines critical needs in families with rare/undiagnosed diseases, provided a framework for interview guide development and transcript analysis (Pelentsov et al in Disabil Health J 8(4):475-491, 2015. https://doi.org/10.1016/J.DHJO.2015.03.009 ). A deductive, iterative coding approach was used to identify common unifying themes. Fourteen parents from 13 families were interviewed. The average child's age was 11 years (range 3-18) and an average 63% of their life had been spent searching for a diagnosis. Our analysis found that alignment or misalignment of parent and child needs impact the trajectory of the diagnostic search. When needs and desires align, reevaluation of a decision to pursue a diagnosis is limited. However, when there is conflict between parent and child desires, there is reevaluation, and often a pause, in the search. This tension is exacerbated when children are adolescents and attempting to balance their dependence on parents for medical care with a natural desire for independence. Our results provide novel insights into the roles of adolescents in the diagnostic odyssey. The tension between desired and realistic developmental outcomes for parents and adolescents impacts if, and how, the search for a diagnosis progresses.
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