70 research outputs found
Metachromatic Leukodystrophy: A Case of Triplets With the Late Infantile Variant and a Systematic Review of the Literature
Metachromatic Leukodystrophy is a rare disorder with great clinical variability. We report the first case of triplets with the late infantile form of the disease and their systematic progression of symptoms. We reviewed the literature and identified all human studies that reported new cases since 1921. We analyzed survival by decade to assess the impact of historical changes in management of care. Mean age at death and 5-year survival from onset of symptoms for late infantile, juvenile and adult phenotype were 4.2 years and 24.9%, 17.4 years and 70.3%, and 43.1 years and 88.6% respectively. 5-year survival of cases reported after 1990 was significantly better than cases reported before 1970 in all subtypes of metachromatic leukodystrophy (late infantile: 52% vs. 14%, juvenile: 100% vs. 46%, adult: 95% vs. 67%). Survival in the late infantile subtype was worse than in other subtypes. Survival significantly improved over time in all subtypes
The optical counterpart to gamma-ray burst GRB970228 observed using the Hubble Space Telescope
Although more than 2,000 astronomical gamma-ray bursts (GRBs) have been
detected, and numerous models proposed to explain their occurrence, they have
remained enigmatic owing to the lack of an obvious counterpart at other
wavelengths. The recent ground-based detection of a transient source in the
vicinity of GRB 970228 may therefore have provided a breakthrough. The optical
counterpart appears to be embedded in an extended source which, if a galaxy as
has been suggested, would lend weight to those models that place GRBs at
cosmological distances. Here we report the observations using the Hubble Space
Telescope of the transient counterpart and extended source 26 and 39 days after
the initial gamma-ray outburst. We find that the counterpart has faded since
the initial detection (and continues to fade), but the extended source exhibits
no significant change in brightness between the two dates of observations
reported here. The size and apparent constancy between the two epochs of HST
observations imply that it is extragalactic, but its faintness makes a
definitive statement about its nature difficult. Nevertheless, the decay
profile of the transient source is consistent with a popular impulsive-fireball
model, which assumes a merger between two neutron stars in a distant galaxy.Comment: 11 pages + 2 figures. To appear in Nature (29 May 1997 issue
Building institutions for an effective health system: lessons from China's experience with rural health reform
This paper is concerned with the management of health system changes aimed at substantially increasing the access to safe and effective health services. It argues that an effective health sector relies on trust-based relationships between users, providers and funders of health services, and that one of the major challenges governments face is to construct institutional arrangements within which these relationships can be embedded. It presents the case of China, which is implementing an ambitious health reform, drawing on a series of visits to rural counties by the author over a 10-year period. It illustrates how the development of reform strategies has been a response both to the challenges arising from the transition to a market economy and the result of actions by different actors, which have led to the gradual creation of increasingly complex institutions. The overall direction of change has been strongly influenced by the efforts made by the political leadership to manage a transition to a modern economy which provides at least some basic benefits to all. The paper concludes that the key lessons for other countries from China’s experience with health system reform are less about the detailed design of specific interventions than about its approach to the management of institution-building in a context of complexity and rapid change.ESR
Elevated Cerebral Spinal Fluid Cytokine Levels in Boys with Cerebral Adrenoleukodystrophy Correlates with MRI Severity
Background: X-linked adrenoleukodystrophy (ALD) is a metabolic, peroxisomal disease that results from a mutation in the ABCD1 gene. The most severe course of ALD progression is the cerebral inflammatory and demyelinating form of the disease, cALD. To date there is very little information on the cytokine mediators in the cerebral spinal fluid (CSF) of these boys. Methodology/Principal Findings: Measurement of 23 different cytokines was performed on CSF and serum of boys with cerebral ALD and patients without ALD. Significant elevations in CSF IL-8 (29.362.2 vs 12.861.1 pg/ml, p = 0.0001), IL-1ra (166630 vs 8.666.5 pg/ml, p = 0.005), MCP-1 (610647 vs 328634 pg/ml, p = 0.002), and MIP-1b (14.261.3 vs 2.061.4 pg/ml, p,0.0001) were found in boys with cALD versus the control group. The only serum cytokine showing an elevation in the ALD group was SDF-1 (21246155 vs 11756125 pg/ml, p = 0.0001). The CSF cytokines of IL-8 and MCP-1b correlated with the Loes MRI severity score (p = 0.04 and p = 0.008 respectively), as well as the serum SDF-1 level (p = 0.002). Finally, CSF total protein was also significantly elevated in boys with cALD and correlated with both IL-8, MCP-1b (p = 0.0001 for both), as well as Loes MRI severity score (p = 0.0007). Conclusions/Significance: IL-8, IL-1ra, MCP-1, MIP-1b and CSF total protein were significantly elevated in patients with cALD; IL-8, MCP-1b, and CSF total protein levels correlated with disease severity determined by MRI. This is the largest repor
The common marmoset genome provides insight into primate biology and evolution
We report the whole-genome sequence of the common marmoset (Callithrix jacchus). The 2.26-Gb genome of a female marmoset was assembled using Sanger read data (6×) and a whole-genome shotgun strategy. A first analysis has permitted comparison with the genomes of apes and Old World monkeys and the identification of specific features that might contribute to the unique biology of this diminutive primate, including genetic changes that may influence body size, frequent twinning and chimerism. We observed positive selection in growth hormone/insulin-like growth factor genes (growth pathways), respiratory complex I genes (metabolic pathways), and genes encoding immunobiological factors and proteases (reproductive and immunity pathways). In addition, both protein-coding and microRNA genes related to reproduction exhibited evidence of rapid sequence evolution. This genome sequence for a New World monkey enables increased power for comparative analyses among available primate genomes and facilitates biomedical research application. © 2014 Nature America, Inc
Small Molecule, Non-Peptide p75NTR Ligands Inhibit Aβ-Induced Neurodegeneration and Synaptic Impairment
The p75 neurotrophin receptor (p75NTR) is expressed by neurons particularly vulnerable in Alzheimer's disease (AD). We tested the hypothesis that non-peptide, small molecule p75NTR ligands found to promote survival signaling might prevent Aβ-induced degeneration and synaptic dysfunction. These ligands inhibited Aβ-induced neuritic dystrophy, death of cultured neurons and Aβ-induced death of pyramidal neurons in hippocampal slice cultures. Moreover, ligands inhibited Aβ-induced activation of molecules involved in AD pathology including calpain/cdk5, GSK3β and c-Jun, and tau phosphorylation, and prevented Aβ-induced inactivation of AKT and CREB. Finally, a p75NTR ligand blocked Aβ-induced hippocampal LTP impairment. These studies support an extensive intersection between p75NTR signaling and Aβ pathogenic mechanisms, and introduce a class of specific small molecule ligands with the unique ability to block multiple fundamental AD-related signaling pathways, reverse synaptic impairment and inhibit Aβ-induced neuronal dystrophy and death
Interchromosomal Duplications on the Bactrocera oleae Y Chromosome Imply a Distinct Evolutionary Origin of the Sex Chromosomes Compared to Drosophila
BACKGROUND: Diptera have an extraordinary variety of sex determination mechanisms, and Drosophila melanogaster is the paradigm for this group. However, the Drosophila sex determination pathway is only partially conserved and the family Tephritidae affords an interesting example. The tephritid Y chromosome is postulated to be necessary to determine male development. Characterization of Y sequences, apart from elucidating the nature of the male determining factor, is also important to understand the evolutionary history of sex chromosomes within the Tephritidae. We studied the Y sequences from the olive fly, Bactrocera oleae. Its Y chromosome is minute and highly heterochromatic, and displays high heteromorphism with the X chromosome. METHODOLOGY/PRINCIPAL FINDINGS: A combined Representational Difference Analysis (RDA) and fluorescence in-situ hybridization (FISH) approach was used to investigate the Y chromosome to derive information on its sequence content. The Y chromosome is strewn with repetitive DNA sequences, the majority of which are also interdispersed in the pericentromeric regions of the autosomes. The Y chromosome appears to have accumulated small and large repetitive interchromosomal duplications. The large interchromosomal duplications harbour an importin-4-like gene fragment. Apart from these importin-4-like sequences, the other Y repetitive sequences are not shared with the X chromosome, suggesting molecular differentiation of these two chromosomes. Moreover, as the identified Y sequences were not detected on the Y chromosomes of closely related tephritids, we can infer divergence in the repetitive nature of their sequence contents. CONCLUSIONS/SIGNIFICANCE: The identification of Y-linked sequences may tell us much about the repetitive nature, the origin and the evolution of Y chromosomes. We hypothesize how these repetitive sequences accumulated and were maintained on the Y chromosome during its evolutionary history. Our data reinforce the idea that the sex chromosomes of the Tephritidae may have distinct evolutionary origins with respect to those of the Drosophilidae and other Dipteran families
Large-Scale Pathway-Based Analysis of Bladder Cancer Genome-Wide Association Data from Five Studies of European Background
Pathway analysis of genome-wide association studies (GWAS) offer a unique opportunity to collectively evaluate genetic variants with effects that are too small to be detected individually. We applied a pathway analysis to a bladder cancer GWAS containing data from 3,532 cases and 5,120 controls of European background (n = 5 studies). Thirteen hundred and ninety-nine pathways were drawn from five publicly available resources (Biocarta, Kegg, NCI-PID, HumanCyc, and Reactome), and we constructed 22 additional candidate pathways previously hypothesized to be related to bladder cancer. In total, 1421 pathways, 5647 genes and ∼90,000 SNPs were included in our study. Logistic regression model adjusting for age, sex, study, DNA source, and smoking status was used to assess the marginal trend effect of SNPs on bladder cancer risk. Two complementary pathway-based methods (gene-set enrichment analysis [GSEA], and adapted rank-truncated product [ARTP]) were used to assess the enrichment of association signals within each pathway. Eighteen pathways were detected by either GSEA or ARTP at P≤0.01. To minimize false positives, we used the I2 statistic to identify SNPs displaying heterogeneous effects across the five studies. After removing these SNPs, seven pathways (‘Aromatic amine metabolism’ [PGSEA = 0.0100, PARTP = 0.0020], ‘NAD biosynthesis’ [PGSEA = 0.0018, PARTP = 0.0086], ‘NAD salvage’ [PARTP = 0.0068], ‘Clathrin derived vesicle budding’ [PARTP = 0.0018], ‘Lysosome vesicle biogenesis’ [PGSEA = 0.0023, PARTP<0.00012], ’Retrograde neurotrophin signaling’ [PGSEA = 0.00840], and ‘Mitotic metaphase/anaphase transition’ [PGSEA = 0.0040]) remained. These pathways seem to belong to three fundamental cellular processes (metabolic detoxification, mitosis, and clathrin-mediated vesicles). Identification of the aromatic amine metabolism pathway provides support for the ability of this approach to identify pathways with established relevance to bladder carcinogenesis
Measuring Health Utilities in Children and Adolescents: A Systematic Review of the Literature.
BACKGROUND: The objective of this review was to evaluate the use of all direct and indirect methods used to estimate health utilities in both children and adolescents. Utilities measured pre- and post-intervention are combined with the time over which health states are experienced to calculate quality-adjusted life years (QALYs). Cost-utility analyses (CUAs) estimate the cost-effectiveness of health technologies based on their costs and benefits using QALYs as a measure of benefit. The accurate measurement of QALYs is dependent on using appropriate methods to elicit health utilities. OBJECTIVE: We sought studies that measured health utilities directly from patients or their proxies. We did not exclude those studies that also included adults in the analysis, but excluded those studies focused only on adults. METHODS AND FINDINGS: We evaluated 90 studies from a total of 1,780 selected from the databases. 47 (52%) studies were CUAs incorporated into randomised clinical trials; 23 (26%) were health-state utility assessments; 8 (9%) validated methods and 12 (13%) compared existing or new methods. 22 unique direct or indirect calculation methods were used a total of 137 times. Direct calculation through standard gamble, time trade-off and visual analogue scale was used 32 times. The EuroQol EQ-5D was the most frequently-used single method, selected for 41 studies. 15 of the methods used were generic methods and the remaining 7 were disease-specific. 48 of the 90 studies (53%) used some form of proxy, with 26 (29%) using proxies exclusively to estimate health utilities. CONCLUSIONS: Several child- and adolescent-specific methods are still being developed and validated, leaving many studies using methods that have not been designed or validated for use in children or adolescents. Several studies failed to justify using proxy respondents rather than administering the methods directly to the patients. Only two studies examined missing responses to the methods administered with respect to the patients' ages
Finishing the euchromatic sequence of the human genome
The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead
- …