Mining new sources of natural history observations for disease interactions.
Ontology highlight
ABSTRACT:
SUBMITTER: Kido A
PROVIDER: S-EPMC6980919 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe natural history of patients with moderate aortic stenosis (AS) is poorly understood. We aimed to determine the long-term outcomes of patients with moderate AS.MethodsWe examined patients with moderate AS defined by echocardiography in our healthcare system, and performed survival analyses for occurrence of death, heart failure (HF) hospitalization, and progression of AS, with accounting for symptoms, left ventricular dysfunction, and comorbidities.ResultsWe examined 729 patients with moderate AS (median age, 76 years; 59.9 % men) with a median follow-up of 5.0 years (interquartile range: 2.0 to 8.1 years). The 5-year overall survival was 52.3 % (95 % confidence interval [CI]: 48.6 % to 56.0 %) and survival free of death or HF hospitalization was 43.2 % (95 % CI: 39.5 % to 46.9 %). Worse New York Heart Association (NYHA) functional class was associated with poor long-term survival, with mortality rates ranging from 7.9 % (95 % CI: 6.6-9.2 %) to 25.2 % (95 % CI: 20.2-30.3 %) per year. Among patients with minimal or no symptoms, no futility markers, and preserved left ventricular function, 5-year overall survival was 71.9 % (95 % CI: 66.4-77.4 %) and survival free of death or HF hospitalization was 61.4 % (95 % CI: 55.5-67.3 %). Risk factors associated with adverse events were age, NYHA class, low ejection fraction and high aortic valve velocity (all p < 0.05).ConclusionsPatients with moderate AS are at significant risk of death. Our findings highlight the need for more study into appropriate therapeutic interventions to improve the prognosis of these patients.
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Project description: Not available
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Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in children. The global prevalence of pediatric NAFLD from general populations is 7.6%. In obese children, the prevalence is higher in Asia. NAFLD has a strong heritable component based on ethnic difference in the prevalence and clustering within families. Genetic polymorphisms of patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily member 2, and glucokinase regulatory protein (GCKR) are associated with the risk of NAFLD in children. Variants of PNPLA3 and GCKR are more common in Asians. Alterations of the gut microbiome might contribute to the pathogenesis of NAFLD. High fructose intake increases the risk of NAFLD. Liver fibrosis is a poor prognostic factor for disease progression to cirrhosis. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction are more accurate for steatosis quantification than ultrasound. Noninvasive imaging methods to assess liver fibrosis, such as transient elastography, shear-wave elastography, and magnetic resonance elastography are useful in predicting advanced fibrosis, but they need further validation. Longitudinal follow-up studies into adulthood are needed to better understand the natural history of pediatric NAFLD.
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Project description:A new stick insect of the genus Orthomeria Kirby, 1904 (Phasmatodea, Aschiphasmatidae) is described from the Philippines. Orthomeria (Orthomeria) kangi sp. n. is readily distinguished from all other congeners by the distinctive blood red colouration of the costal region of the hind wings. Major features of the external morphology of adults, eggs, and first-instar nymphs are illustrated. Locomotory attachment pads are of the smooth type with irregular microgrooves on the contact surface. An unusual condition of male terminalia is the absence of tergal thorn pads on segment 10. The male clasping organs are represented by an elongated vomer terminating in a prominent spine, and by incurved cerci featuring a bilobed apex equipped with a sharp blade-like ridge. Intraspecific variation in body colouration and hind wing length occurs in females. The new species lives at 400-650 m elevation in the surroundings of the Sablang and Tuba regions, in the Benguet Province of Luzon island. Host plants include Ficus spp. (Moraceae), and Pipturus spp. and Leucosyke spp. (Urticaceae). Observations on the mating and defensive behaviour are presented. Orthomeria (Orthomeria) catadromus (Westwood, 1859) is recognised as a junior synonym of Orthomeria (Orthomeria) pandora (Westwood, 1859), syn. n. A lectotype is designated for both species. Finally, an updated identification key to the species of the subgenus Orthomeria is provided.
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Project description:Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus-Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value.
| S-EPMC4492172 | biostudies-other
Project description:BackgroundCanavan disease (CD, MIM # 271900) is a rare and devastating leukodystrophy of early childhood. To identify clinical features that could serve as endpoints for treatment trials, the clinical course of CD was studied retrospectively and prospectively in 23 CD patients. Results were compared with data of CD patients reported in three prior large series. Kaplan Meier survival analysis including log rank test was performed for pooled data of 82 CD patients (study cohort and literature patients).ResultsOnset of symptoms was between 0 and 6 months. Psychomotor development of patients was limited to abilities that are usually gained within the first year of life. Macrocephaly became apparent between 4 and 18 months of age. Seizure frequency was highest towards the end of the first decade. Ethnic background was more diverse than in studies previously reported. A CD severity score with assessment of 11 symptoms and abilities was developed.ConclusionsEarly hallmarks of CD are severe psychomotor disability and macrocephaly that develop within the first 18 months of life. While rare in the first year of life, seizures increase in frequency over time in most patients. CD occurs more frequently outside Ashkenazi Jewish communities than previously reported. Concordance of phenotypes between siblings but not patients with identical ASPA mutations suggest the influence of yet unknown modifiers. A CD severity score may allow for assessment of CD disease severity both retrospectively and prospectively.
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Project description:The Wnt signaling is one of the major pathways known to regulate embryonic development, tissue renewal and regeneration in multicellular organisms. Dysregulations of the pathway are a common cause of several types of cancer and other diseases, such as osteoporosis and rheumatoid arthritis. This makes Wnt signaling an important therapeutic target. Small molecule activators and inhibitors of signaling pathways are important biomedical tools which allow one to harness signaling processes in the organism for therapeutic purposes in affordable and specific ways. Natural products are a well known source of biologically active small molecules with therapeutic potential. In this article, we provide an up-to-date overview of existing small molecule modulators of the Wnt pathway derived from natural products. In the first part of the review, we focus on Wnt pathway activators, which can be used for regenerative therapy in various tissues such as skin, bone, cartilage and the nervous system. The second part describes inhibitors of the pathway, which are desired agents for targeted therapies against different cancers. In each part, we pay specific attention to the mechanisms of action of the natural products, to the models on which they were investigated, and to the potential of different taxa to yield bioactive molecules capable of regulating the Wnt signaling.
| S-EPMC7140537 | biostudies-literature
Project description:Tay-Sachs disease (TSD) is a fatal neurodegenerative disease caused by a deficiency of the enzyme β-N-acetylhexosaminidase A (HexA). TSD naturally occurs in Jacob sheep is the only experimental model of TSD. TSD in sheep recapitulates neurologic features similar to juvenile onset and late onset TSD patients. Due to the paucity of human literature on pathology of TSD, a better natural history in the sheep TSD brain, which is on the same order of magnitude as a child's, is necessary for evaluating therapy and characterizing the pathological events that occur. To provide clinicians and researchers with a clearer understanding of longitudinal pathology in patients, we compare spectrum of clinical signs and brain pathology in mildly symptomatic (3-months), moderately symptomatic (6-months), or severely affected TSD sheep (humane endpoint at ~9-months of age). Increased GM2 ganglioside in the CSF of TSD sheep and a TSD specific biomarker on MRS (taurine) correlate with disease severity. Microglial activation and reactive astrocytes were observed globally on histopathology in TSD sheep with a widespread reduction in oligodendrocyte density. Myelination is reduced primarily in the forebrain illustrated by loss of white matter on MRI. GM2 and GM3 ganglioside were increased and distributed differently in various tissues. The study of TSD in the sheep model provides a natural history to shed light on the pathophysiology of TSD, which is of utmost importance due to novel therapeutics being assessed in human patients.
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Project description:The long term outcome of drug related liver disease is unknown.To study the natural history of histologically proved drug induced hepatotoxicity.110 patients with liver biopsies coded either as drug induced liver disease or hepatitis/cholestasis of unknown aetiology were identified from hospital records 1978-1996. Review of case notes and histology identified 44 patients with definite drug induced hepatotoxicity. Forty surviving patients were invited to attend a follow up clinic. History, examination, full liver screen, and isotope and ultrasound liver scans were repeated in all patients. Repeat liver biopsies were offered to patients with abnormal liver tests.Presentation at index biopsy was jaundice in 24 patients, abnormal liver tests in 17, and hepatic failure in three. Antibiotics (n=13) and non-steroidal anti-inflammatory drugs (n=11) were the most common drugs implicated. Initial histology showed acute hepatitis in six, chronic hepatitis in 20, and cholestasis in 18. At 1-19 years (median 5 years) follow up, 13/33 (39%) patients had persistent significant abnormalities in their liver blood tests and/or scans. Three of the five repeat liver biopsies performed showed significant abnormalities. Factors predicting persistence or development of chronic liver disease were fibrosis and continued exposure to the drug.Drugs should be considered in the differential diagnosis of abnormal liver function and/or histology, as failure to withdraw the offending drug is associated with a high risk of persistent liver damage.
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Project description:CoRDS, or the Coordination of Rare Diseases at Sanford, is based at Sanford Research in Sioux Falls, South Dakota. It provides researchers with a centralized, international patient registry for all rare diseases. This program allows patients and researchers to connect as easily as possible to help advance treatments and cures for rare diseases. The CoRDS team works with patient advocacy groups, individuals and researchers to help in the advancement of research in over 7,000 rare diseases. The registry is free for patients to enroll and researchers to access. Visit sanfordresearch.org/CoRDS to enroll.
| 2140190 | ecrin-mdr-crc