531 research outputs found

    Child Care and Children With Special Needs: Challenges for Low Income Families [Report]

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    Findings from this mixed methods study include: Parents of young children with special needs face significant challenges finding and keeping child care arrangements for their child. Parents report significant problems with the child care arrangements they have used for their child with special needs. There are significant programmatic and financial barriers to supporting parents of children with special needs so they can work, and balance work and family. The combination of all of these problems and the particular demands of caring for a child with special needs often result in employment problems and job instability. Families of children with special needs face more economic difficulties (poverty, food and rent insecurity, lack of health insurance) than do families of children without special needs. Certain types of disabilities have a greater impact on the number of child care and work problems than others. Having a child with multiple special needs or having more than one child with special needs significantly increases the likelihood of employment difficulties and job instability

    A genome-wide association study follow-up suggests a possible role for PPARG in systemic sclerosis susceptibility

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    Introduction: A recent genome-wide association study (GWAS) comprising a French cohort of systemic sclerosis (SSc) reported several non-HLA single-nucleotide polymorphisms (SNPs) showing a nominal association in the discovery phase. We aimed to identify previously overlooked susceptibility variants by using a follow-up strategy.<p></p> Methods: Sixty-six non-HLA SNPs showing a P value <10-4 in the discovery phase of the French SSc GWAS were analyzed in the first step of this study, performing a meta-analysis that combined data from the two published SSc GWASs. A total of 2,921 SSc patients and 6,963 healthy controls were included in this first phase. Two SNPs, PPARG rs310746 and CHRNA9 rs6832151, were selected for genotyping in the replication cohort (1,068 SSc patients and 6,762 healthy controls) based on the results of the first step. Genotyping was performed by using TaqMan SNP genotyping assays. Results: We observed nominal associations for both PPARG rs310746 (PMH = 1.90 × 10-6, OR, 1.28) and CHRNA9 rs6832151 (PMH = 4.30 × 10-6, OR, 1.17) genetic variants with SSc in the first step of our study. In the replication phase, we observed a trend of association for PPARG rs310746 (P value = 0.066; OR, 1.17). The combined overall Mantel-Haenszel meta-analysis of all the cohorts included in the present study revealed that PPARG rs310746 remained associated with SSc with a nominal non-genome-wide significant P value (PMH = 5.00 × 10-7; OR, 1.25). No evidence of association was observed for CHRNA9 rs6832151 either in the replication phase or in the overall pooled analysis.<p></p> Conclusion: Our results suggest a role of PPARG gene in the development of SSc

    Comprehensive analysis of the major histocompatibility complex in systemic sclerosis identifies differential HLA associations by clinical and serological subtypes

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    Objective: The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods: 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results: Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1∗11:04 and HLA-DPB1∗13:01, and revealed a novel association of HLA-B∗08:01. Stratified analyses showed specific associations of HLA-DQA1∗02:01 with lcSSc, and an exclusive association of HLA-DQA1∗05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1∗08:01 and confirmed the previously reported association of HLA-DRB1∗07:01 with ACA-positive patients, as opposed to the HLA-DPA1∗02:01 and HLA-DQB1∗03:01 alleles associated with ATA presentation. Conclusions: This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression

    Do replication forks control late origin firing in Saccharomyces cerevisiae?

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    Recent studies of eukaryotic DNA replication timing profiles suggest that the time-dependent rate of origin firing, I(t), has a universal shape, which ensures a reproducible replication completion time. However, measurements of I(t) are based on population averages, which may bias the shape of the I(t) because of imperfect cell synchrony and cell-to-cell variability. Here, we measure the population-averaged I(t) profile from synchronized Saccharomyces cerevisiae cells using DNA combing and we extract the single-cell I(t) profile using numerical deconvolution. The single cell I(t) and the population-averaged I(t) extracted from DNA combing and replication timing profiles are similar, indicating a genome scale invariance of the replication process, and excluding cell-to-cell variability in replication time as an explanation for the shape of I(t). The single cell I(t) correlates with fork density in wild-type cells, which is specifically loosened in late S phase in the clb5Δ mutant. A previously proposed numerical model that reproduces the wild-type I(t) profile, could also describe the clb5Δ mutant I(t) once modified to incorporate the decline in CDK activity and the looser dependency of initiation on fork density in the absence of Clb5p. Overall, these results suggest that the replication forks emanating from early fired origins facilitate origin firing in later-replicating regions

    A pre-Caloris synchronous rotation for Mercury

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    The planet Mercury is locked in a spin-orbit resonance where it rotates three times about its spin axis for every two orbits about the Sun. The current explanation for this unique state assumes that the initial rotation of this planet was prograde and rapid, and that tidal torques decelerated the planetary spin to this resonance. When core-mantle boundary friction is accounted for, capture into the 3/2 resonance occurs with a 26% probability, but the most probable outcome is capture into one of the higher-order resonances. Here we show that if the initial rotation of Mercury were retrograde, this planet would be captured into synchronous rotation with a 68% probability. Strong spatial variations of the impact cratering rate would have existed at this time, and these are shown to be consistent with the distribution of pre-Calorian impact basins observed by Mariner 10 and MESSENGER. Escape from this highly stable resonance is made possible by the momentum imparted by large basin-forming impact events, and capture into the 3/2 resonance occurs subsequently under favourable conditions.Comment: Nature Geosci., 201

    Primary Raynaud's phenomenon in an infant: a case report and review of literature

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    Raynaud's phenomenon (RP) is an extremely unusual finding in early infancy. In the present report we describe a one-month-old previously healthy male infant who presented with unilateral acrocyanosis. Although infantile acrocyanosis is known to be a benign and self-resolving condition, it is generally bilateral and symmetric. The unilateral nature of the acrocyanosis was an atypical finding in this infant. Consequently, he was closely monitored to evaluate the progression of his acrocyanosis. Based on his benign clinical course and failure to demonstrate other etiologies contributing to his acrocyanosis, he was diagnosed to have primary RP. Due to the rarity of RP in children, we review the progress in understanding the pathophysiology, epidemiology and management of RP and additionally discuss the differential diagnosis of unilateral and bilateral acrocyanosis in infants

    In vitro and in vivo characterization of highly purified Human Mesothelioma derived cells

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    <p>Abstract</p> <p>Background</p> <p>Malignant pleural mesothelioma is a rare disease known to be resistant to conventional therapies. A better understanding of mesothelioma biology may provide the rationale for new therapeutic strategies. In this regard, tumor cell lines development has been an important tool to study the biological properties of many tumors. However all the cell lines established so far were grown in medium containing at least 10% serum, and it has been shown that primary cell lines cultured under these conditions lose their ability to differentiate, acquire gene expression profiles that differ from that of tissue specific stem cells or the primary tumor they derive from, and in some cases are neither clonogenic nor tumorigenic. Our work was aimed to establish from fresh human pleural mesothelioma samples cell cultures maintaining tumorigenic properties.</p> <p>Methods</p> <p>The primary cell cultures, obtained from four human pleural mesotheliomas, were expanded in vitro in a low serum proliferation-permissive medium and the expression of different markers as well as the tumorigenicity in immunodeficient mice was evaluated.</p> <p>Results</p> <p>The established mesothelioma cell cultures are able to engraft, after pseudo orthotopic intraperitoneal transplantation, in immunodeficient mouse and maintain this ability to after serial transplantation. Our cell cultures were strongly positive for CD46, CD47, CD56 and CD63 and were also strongly positive for some markers never described before in mesothelioma cell lines, including CD55, CD90 and CD99. By real time PCR we found that our cell lines expressed high mRNA levels of typical mesothelioma markers as mesothelin (MSLN) and calretinin (CALB2), and of BMI-1, a stemness marker, and DKK1, a potent Wingless [WNT] inhibitor.</p> <p>Conclusions</p> <p>These cell cultures may provide a valuable in vitro and in vivo model to investigate mesothelioma biology. The identification of new mesothelioma markers may be useful for diagnosis and/or prognosis of this neoplasia as well as for isolation of mesothelioma tumor initiating cells.</p

    Evaluation of unclassified variants in the breast cancer susceptibility genes BRCA1 and BRCA2 using five methods: results from a population-based study of young breast cancer patients

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    Introduction Efforts are ongoing to determine the significance of unclassified variants (UVs) in the breast cancer susceptibility genes BRCA1/BRCA2, but no study has systematically assessed whether women carrying the suspected deleterious UVs have characteristics commonly seen among women carrying known deleterious or disease-causing mutations in BRCA1/BRCA2. Methods We sequenced BRCA1/BRCA2 in 1,469 population-based female breast cancer patients diagnosed between the ages of 20 and 49 years. We used existing literature to classify variants into known deleterious mutations, polymorphic variants, and UVs. The UVs were further classified as high risk or low risk based on five methods: allele frequency, Polyphen algorithm, sequence conservation, Grantham matrix scores, and a combination of the Grantham matrix score and sequence conservation. Furthermore, we examined whether patients who carry the variants classified as high risk using these methods have risk characteristics similar to patients with known deleterious BRCA1/BRCA2 mutations (early age at diagnosis, family history of breast cancer or ovarian cancer, and negative estrogen receptor/progesterone receptor). Results We identified 262 distinct BRCA1/BRCA2 variants, including 147 UVs, in our study population. The BRCA1 UV carriers, but not the BRCA2 UV carriers, who were classified as high risk using each classification method were more similar to the deleterious mutation carriers with respect to family history than those carriers classified as low risk. For example, the odds ratio of having a first-degree family history for the high-risk women classified using Polyphen was 3.39 (95% confidence interval = 1.16 to 9.94) compared with normal/polymorphic BRCA1 carriers. The corresponding odds ratio of low-risk women was 1.53 (95% confidence interval = 1.07 to 2.18). The odds ratio for high-risk women defined by allele frequency was 2.00 (95% confidence interval = 1.14 to 3.51), and that of low-risk women was 1.30 (95% confidence interval = 0.87 to 1.93). Conclusion The results suggest that the five classification methods yielded similar results. Polyphen was particularly better at isolating BRCA1 UV carriers likely to have a family history of breast cancer or ovarian cancer, and may therefore help to classify BRCA1 UVs. Our study suggests that these methods may not be as successful in classifying BRCA2 UVs
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