74 research outputs found
Mucopolysaccharidosis VI
Mucopolysaccharidosis VI (MPS VI) is a lysosomal storage disease with progressive multisystem involvement, associated with a deficiency of arylsulfatase B leading to the accumulation of dermatan sulfate. Birth prevalence is between 1 in 43,261 and 1 in 1,505,160 live births. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The characteristic skeletal dysplasia includes short stature, dysostosis multiplex and degenerative joint disease. Rapidly progressing forms may have onset from birth, elevated urinary glycosaminoglycans (generally >100 μg/mg creatinine), severe dysostosis multiplex, short stature, and death before the 2nd or 3rd decades. A more slowly progressing form has been described as having later onset, mildly elevated glycosaminoglycans (generally <100 μg/mg creatinine), mild dysostosis multiplex, with death in the 4th or 5th decades. Other clinical findings may include cardiac valve disease, reduced pulmonary function, hepatosplenomegaly, sinusitis, otitis media, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease, and inguinal or umbilical hernia. Although intellectual deficit is generally absent in MPS VI, central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The disorder is transmitted in an autosomal recessive manner and is caused by mutations in the ARSB gene, located in chromosome 5 (5q13-5q14). Over 130 ARSB mutations have been reported, causing absent or reduced arylsulfatase B (N-acetylgalactosamine 4-sulfatase) activity and interrupted dermatan sulfate and chondroitin sulfate degradation. Diagnosis generally requires evidence of clinical phenotype, arylsulfatase B enzyme activity <10% of the lower limit of normal in cultured fibroblasts or isolated leukocytes, and demonstration of a normal activity of a different sulfatase enzyme (to exclude multiple sulfatase deficiency). The finding of elevated urinary dermatan sulfate with the absence of heparan sulfate is supportive. In addition to multiple sulfatase deficiency, the differential diagnosis should also include other forms of MPS (MPS I, II IVA, VII), sialidosis and mucolipidosis. Before enzyme replacement therapy (ERT) with galsulfase (Naglazyme®), clinical management was limited to supportive care and hematopoietic stem cell transplantation. Galsulfase is now widely available and is a specific therapy providing improved endurance with an acceptable safety profile. Prognosis is variable depending on the age of onset, rate of disease progression, age at initiation of ERT and on the quality of the medical care provided
Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrogen receptor beta - regulation by selective estrogen receptor modulators and importance in breast cancer
Estrogens display intriguing tissue-selective action that is of great biomedical importance in the development of optimal therapeutics for the prevention and treatment of breast cancer, for menopausal hormone replacement, and for fertility regulation. Certain compounds that act through the estrogen receptor (ER), now referred to as selective estrogen receptor modulators (SERMs), can demonstrate remarkable differences in activity in the various estrogen target tissues, functioning as agonists in some tissues but as antagonists in others. Recent advances elucidating the tripartite nature of the biochemical and molecular actions of estrogens provide a good basis for understanding these tissue-selective actions. As discussed in this thematic review, the development of optimal SERMs should now be viewed in the context of two estrogen receptor subtypes, ERα and ERβ, that have differing affinities and responsiveness to various SERMs, and differing tissue distribution and effectiveness at various gene regulatory sites. Cellular, biochemical, and structural approaches have also shown that the nature of the ligand affects the conformation assumed by the ER-ligand complex, thereby regulating its state of phosphorylation and the recruitment of different coregulator proteins. Growth factors and protein kinases that control the phosphorylation state of the complex also regulate the bioactivity of the ER. These interactions and changes determine the magnitude of the transcriptional response and the potency of different SERMs. As these critical components are becoming increasingly well defined, they provide a sound basis for the development of novel SERMs with optimal profiles of tissue selectivity as medical therapeutic agents
ERBB2 in Cat Mammary Neoplasias Disclosed a Positive Correlation between RNA and Protein Low Expression Levels: A Model for erbB-2 Negative Human Breast Cancer
Human ERBB2 is a proto-oncogene that codes for the erbB-2 epithelial growth factor receptor. In human breast cancer (HBC), erbB-2 protein overexpression has been repeatedly correlated with poor prognosis. In more recent works, underexpression of this gene has been described in HBC. Moreover, it is also recognised that oncogenes that are commonly amplified or deleted encompass point mutations, and some of these are associated with HBC. In cat mammary lesions (CMLs), the overexpression of ERBB2 (27%–59.6%) has also been described, mostly at the protein level and although cat mammary neoplasias are considered to be a natural model of HBC, molecular information is still scarce. In the present work, a cat ERBB2 fragment, comprising exons 10 to 15 (ERBB2_10–15) was achieved for the first time. Allelic variants and genomic haplotype analyses were also performed, and differences between normal and CML populations were observed. Three amino acid changes, corresponding to 3 non-synonymous genomic sequence variants that were only detected in CMLs, were proposed to damage the 3D structure of the protein. We analysed the cat ERBB2 gene at the DNA (copy number determination), mRNA (expression levels assessment) and protein levels (in extra- and intra protein domains) in CML samples and correlated the last two evaluations with clinicopathological features. We found a positive correlation between the expression levels of the ERBB2 RNA and erbB-2 protein, corresponding to the intracellular region. Additionally, we detected a positive correlation between higher mRNA expression and better clinical outcome. Our results suggest that the ERBB2 gene is post-transcriptionally regulated and that proteins with truncations and single point mutations are present in cat mammary neoplastic lesions. We would like to emphasise that the recurrent occurrence of low erbB-2 expression levels in cat mammary tumours, suggests the cat mammary neoplasias as a valuable model for erbB-2 negative HBC.POCI/CVT/62940/2004 and by the PhD grants (SFRH/BD/23406/2005 and SFRH/BD/31754/2006, of the Science and Technology Foundation (FCT) from Portugal
A systematic review of physical activity and sedentary behaviour research in the oil-producing countries of the Arabian Peninsula
A Systematic Review and Meta-analysis of the Impact of Mindfulness-Based Interventions on the Well-Being of Healthcare Professionals
Efforts to improve the wellbeing of healthcare professionals include mindfulness-based interventions (MBIs). To understand the value of such initiatives, we conducted a systematic review and meta-analysis of empirical studies pertaining to the use of MBIs with healthcare professionals. Databases were reviewed from the start of records to January 2016 (PROSPERO registration number: CRD42016032899). Eligibility criteria included empirical analyses of wellbeing outcomes acquired in relation to MBIs. Forty-two papers met the eligibility criteria, consisting of a total of 2,101 participants. Studies were examined for two broad classes of wellbeing outcomes: (a) “negative” mental health measures such as anxiety, depression, and stress; (b) “positive” indices of wellbeing, such as life satisfaction, together with outcomes associated with wellbeing, such as emotional intelligence. MBIs were generally associated with positive outcomes in relation to most measures, and mindfulness does appear to improve the wellbeing of healthcare professionals. However, the quality of the studies was inconsistent, so further research is needed, particularly high-quality randomised control trials
Dynamics of recruitment and establishment of the invasive seaweed Codium fragile within an eelgrass habitat
Can an old alien benefit from rising ocean temperatures? An experimental and field study on the growth and local distribution of Codium fragile subsp. fragile (Chlorophyta)
Codium fragile subsp. fragile (hereafter C. fragile) is a widespread non-native chlorophyte. Experimental and observational approaches were used to examine the influence of temperature on its growth and local distribution in southwestern Norway, where it has been established for over 80 years. Growth was measured in laboratory experiments at current and predicted seasonal minimum and maximum seawater temperatures, and under natural conditions by recording length over 1 year in the field. The results indicated that if temperatures increase, C. fragile growth rate may increase in spring, but not in mid-autumn/winter due to low light. Thallus fragmentation was common in autumn/winter in the field, but very rare in the winter-temperature laboratory experiment, indicating that low temperature is not the only driver. Growth occurred at temperatures which are reported as too low for growth in other locations, suggesting that C. fragile can acclimatise/adapt to local temperature regimes. Local distribution was examined by surveying abundance using categories based on the number of thalli and their arrangement (scattered/patch/zone) at 46 stations from 2011 to 2016. Codium fragile colonised the stations relatively often, but was frequently lost from sites with only bedrock compared to sites with stony substratum present (cobbles/boulders). It was more likely to be consistently present at sites with stones and could form dominant patches of canopy in the upper sublittoral on this substratum. An increase in the number of stations with C. fragile present was seen after two mild winters, suggesting that higher minimum temperatures may increase site occupancy of C. fragile in this region
Can an old alien benefit from rising ocean temperatures? An experimental and field study on the growth and local distribution of Codium fragile subsp. fragile (Chlorophyta)
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