1,780 research outputs found
Preferential associated anomalies in 818 cases of microtia in South america
The etiology of microtia remains unknown in most cases. The identification of patterns of associated anomalies (i.e., other anomalies that occur with a given congenital anomaly in a higher than expected frequency), is a methodology that has been used for research into the etiology of birth defects. We conducted a study based on cases of microtia that were diagnosed from more than 5 million live (LB)- and stillbirths (SB) examined in hospitals participating in ECLAMC (Latin American Collaborative Study of Congenital Malformations) between 1967 and 2009. We identified 818 LB and SB with microtia and at least one additional non-related major congenital anomaly (cases) and 15,969 LB and SB with two or more unrelated major congenital anomalies except microtia (controls). A logistic regression analysis was performed to identify the congenital anomalies preferentially associated with microtia. Preferential associations were observed for 10 congenital anomalies, most of them in the craniofacial region, including facial asymmetry, choanal atresia, and eyelid colobomata. The analysis by type of microtia showed that for anomalies such as cleft lip and palate, macrostomia, and limb reduction defects, the frequency increased with the severity of the microtia. In contrast, for other anomalies the frequency tended to be the same across all types of microtia. Based on these results we will integrate data on the developmental pathways related to preferentially associated congenital anomalies for future studies investigating the etiology of microtia.Fil: Luquetti, Daniela V.. University of Washington; Estados Unidos. Seattle Children’s Research Institute; Estados UnidosFil: Cox, Thimoty C.. Monash University; Australia. University of Washington; Estados UnidosFil: López Camelo, Jorge Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. CEMIC-CONICET. Centro de Educaciones Médicas e Investigaciones Clínicas "Norberto Quirno". CEMIC-CONICET.; ArgentinaFil: Dutra, Maria da Graça. Instituto Oswaldo Cruz; BrasilFil: Cunningham, Michael L.. University of Washington; Estados Unidos. Seattle Children’s Research Institute; Estados UnidosFil: Castilla, Eduardo Enrique. Centro de Educación Médica e Investigaciones Clínicas “Norberto Quirno”; Argentina. Instituto Oswaldo Cruz; Brasil. Instituto Nacional de Genética Médica Populacional; Brasi
Hepatocellular proliferation in response to agonists of peroxisome proliferator-activated receptor alpha: a role for kupffer cells?
BACKGROUND: It has been proposed that PPARα agonists stimulate Kupffer cells in rodents which in turn, release mitogenic factors leading to hepatic hyperplasia, and eventually cancer. However, Kupffer cells do not express PPARα receptors, and PPARα agonists stimulate hepatocellular proliferation in both TNFα- and TNFα receptor-null mice, casting doubt on the involvement of Kupffer cells in the mitogenic response to PPARα agonists. This study was therefore designed to investigate whether the PPARα agonist PFOA and the Kupffer cell inhibitor methylpalmitate produce opposing effects on hepatocellular proliferation and Kupffer cell activity in vivo, in a manner that would implicate these cells in the mitogenic effects of PPARα agonists. METHODS: Male Sprague-Dawley rats were treated intravenously via the tail vein with methylpalmitate 24 hrs prior to perfluorooctanoic acid (PFOA), and were sacrificed 24 hrs later, one hr after an intraperitoneal injection of bromodeoxyuridine (BrdU). Sera were analyzed for TNFα and IL-1β. Liver sections were stained immunohistochemically and quantified for BrdU incorporated into DNA. RESULTS: Data show that PFOA remarkably stimulated hepatocellular proliferation in the absence of significant changes in the serum levels of either TNFα or IL-1β. In addition, methylpalmitate did not alter the levels of these mitogens in PFOA-treated animals, despite the fact that it significantly blocked the hepatocellular proliferative effect of PFOA. Correlation between hepatocellular proliferation and serum levels of TNFα or IL-1β was extremely poor. CONCLUSION: It is unlikely that mechanisms involving Kupffer cells play an eminent role in the hepatic hyperplasia, and consequently hepatocarcinogenicity attributed to PPARα agonists. This conclusion is based on the above mentioned published data and the current findings showing animals treated with PFOA alone or in combination with methylpalmitate to have similar levels of serum TNFα and IL-1β, which are reliable indicators of Kupffer cell activity, despite a remarkable difference in hepatocellular proliferation
Dysflective cones: Visual function and cone reflectivity in long-term follow-up of acute bilateral foveolitis.
PURPOSE:Confocal adaptive optics scanning laser ophthalmoscope (AOSLO) images provide a sensitive measure of cone structure. However, the relationship between structural findings of diminished cone reflectivity and visual function is unclear. We used fundus-referenced testing to evaluate visual function in regions of apparent cone loss identified using confocal AOSLO images. METHODS:A patient diagnosed with acute bilateral foveolitis had spectral-domain optical coherence tomography (SD-OCT) (Spectralis HRA + OCT system [Heidelberg Engineering, Vista, CA, USA]) images indicating focal loss of the inner segment-outer segment junction band with an intact, but hyper-reflective, external limiting membrane. Five years after symptom onset, visual acuity had improved from 20/80 to 20/25, but the retinal appearance remained unchanged compared to 3 months after symptoms began. We performed structural assessments using SD-OCT, directional OCT (non-standard use of a prototype on loan from Carl Zeiss Meditec) and AOSLO (custom-built system). We also administered fundus-referenced functional tests in the region of apparent cone loss, including analysis of preferred retinal locus (PRL), AOSLO acuity, and microperimetry with tracking SLO (TSLO) (prototype system). To determine AOSLO-corrected visual acuity, the scanning laser was modulated with a tumbling E consistent with 20/30 visual acuity. Visual sensitivity was assessed in and around the lesion using TSLO microperimetry. Complete eye examination, including standard measures of best-corrected visual acuity, visual field tests, color fundus photos, and fundus auto-fluorescence were also performed. RESULTS:Despite a lack of visible cone profiles in the foveal lesion, fundus-referenced vision testing demonstrated visual function within the lesion consistent with cone function. The PRL was within the lesion of apparent cone loss at the fovea. AOSLO visual acuity tests were abnormal, but measurable: for trials in which the stimulus remained completely within the lesion, the subject got 48% correct, compared to 78% correct when the stimulus was outside the lesion. TSLO microperimetry revealed reduced, but detectible, sensitivity thresholds within the lesion. CONCLUSIONS AND IMPORTANCE:Fundus-referenced visual testing proved useful to identify functional cones despite apparent photoreceptor loss identified using AOSLO and SD-OCT. While AOSLO and SD-OCT appear to be sensitive for the detection of abnormal or absent photoreceptors, changes in photoreceptors that are identified with these imaging tools do not correlate completely with visual function in every patient. Fundus-referenced vision testing is a useful tool to indicate the presence of cones that may be amenable to recovery or response to experimental therapies despite not being visible on confocal AOSLO or SD-OCT images
Mechanism of Disease:Recessive ADAMTSL4 Mutations and Craniosynostosis with Ectopia Lentis
Craniosynostosis, the premature fusion of the calvarial bones, has numerous etiologies. Among them, several involve mutations in genes related to the TGFb signaling pathway, a critical molecular mediator of human development. These TGFb pathway-associated craniosynostosis syndromes include Loeys-Dietz syndrome (LDS) and Shprintzen-Goldberg syndrome (SGS). LDS and SGS have many similarities common to fibrillinopathies, specifically Marfan syndrome (MFS), which is caused by mutations in FBN1. Historically discriminating features of MFS from LDS and SGS are (1) the presence of ectopia lentis (the subluxation/dislocation of the ocular lens) and (2) the absence of craniosynostosis. Curiously, several instances of a seemingly novel syndrome involving only craniosynostosis and ectopia lentis have recently been reported to be caused by recessive mutations in ADAMTSL4, a poorly characterized gene as of yet. Here, we report on two new cases of craniosynostosis with ectopia lentis, each harboring recessive mutations in ADAMTSL4. We also discuss a proposed mechanism for the relationship between ADAMTSL4, FBN1, and TGFb pathway-related syndromes.</p
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