Limbal stem cell transplantation: current perspectives

Marwan Raymond Atallah, Sotiria Palioura, Victor L Perez, Guillermo Amescua Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA Abstract: Regeneration of the corneal surface after an epithelial insult involves division, migration, and maturation of a specialized group of stem cells located in the limbus. Several insults, both intrinsic and extrinsic, can precipitate destruction of the delicate microenvironment of these cells, resulting in limbal stem cell deficiency (LSCD). In such cases, reepithelialization fails and conjunctival epithelium extends across the limbus, leading to vascularization, persistent epithelial defects, and chronic inflammation. In partial LSCD, conjunctival epitheliectomy, coupled with amniotic membrane transplantation, could be sufficient to restore a healthy surface. In more severe cases and in total LSCD, stem cell transplantation is currently the best curative option. Before any attempts are considered to perform a limbal stem cell transplantation procedure, the ocular surface must be optimized by controlling causative factors and comorbid conditions. These factors include adequate eyelid function or exposure, control of the ocular surface inflammatory status, and a well-lubricated ocular surface. In cases of unilateral LSCD, stem cells can be obtained from the contralateral eye. Newer techniques aim at expanding cells in vitro or in vivo in order to decrease the need for large limbal resection that may jeopardize the “healthy” eye. Patients with bilateral disease can be treated using allogeneic tissue in combination with systemic immunosuppressive therapy. Another emerging option for this subset of patients is the use of noncorneal cells such as mucosal grafts. Finally, the use of keratoprosthesis is reserved for patients who are not candidates for any of the aforementioned options, wherein the choice of the type of keratoprosthesis depends on the severity of the disease. In summary, limbal stem cell transplantation improves both vision and quality-of-life in patients with ocular surface disorders associated with LSCD, and overall, the use of autologous tissue offers the best results. Future studies aim at improving cellular expansion and finding different sources of stem cells. Keywords: limbal stem cell deficiency (LSCD), simple limbal epithelial transplantation (SLET), cultivated limbal epithelial transplantation (CLET), keratolimbal allograft (KLAL

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Extending the spectrum of Ellis van Creveld syndrome: a large family with a mild mutation in the EVC gene

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is characterized by short limbs, short ribs, postaxial polydactyly, dysplastic nails and teeth and is inherited in an autosomal recessive pattern. We report a family with complex septal cardiac defects, rhizomelic limb shortening, and polydactyly, without the typical lip, dental, and nail abnormalities of EvC. The phenotype was inherited in an autosomal recessive pattern, with one instance of pseudodominant inheritance.</p> <p>Methods</p> <p>Because of the phenotypic overlap with EvC, microsatellite markers were used to test for linkage to the <it>EVC/EVC2 </it>locus. The results did not exclude linkage, so samples were sequenced for mutations.</p> <p>Results</p> <p>We identified a c.1868T>C mutation in <it>EVC</it>, which predicts p.L623P, and was homozygous in affected individuals.</p> <p>Conclusion</p> <p>We conclude that this <it>EVC </it>mutation is hypomorphic and that such mutations can cause a phenotype of cardiac and limb defects that is less severe than typical EvC. <it>EVC </it>mutation analysis should be considered in patients with cardiac and limb malformations, even if they do not manifest typical EvC syndrome.</p

Molecular and clinical analysis of Ellis-van Creveld syndrome in the United Arab Emirates

<p>Abstract</p> <p>Background</p> <p>Ellis-van Creveld (EvC) syndrome is an autosomal recessive chondrodysplastic condition with clinical manifestations that include short-limbs and ribs, postaxial polydactyly and dysplastic nails and teeth. In about two thirds of patients, mutations in either <it>EVC </it>or <it>EVC2 </it>genes have been found to be the underlying cause.</p> <p>Methods</p> <p>In this paper, we describe the molecular (DNA sequencing) and clinical analysis of six children diagnosed with EvC from four different families from the United Arab Emirates (UAE).</p> <p>Results</p> <p>All the children had the common clinical and radiological features of this syndrome. However, DNA sequence analysis of the genes shown to be involved (<it>EVC </it>and <it>EVC2</it>) revealed a novel splice site mutation (c.2047-1G>T) in intron 13 of <it>EVC2 </it>gene in one family. In addition, we confirm previous mutational analyses that showed a truncating mutation in exon 13 of <it>EVC </it>gene (c.1813C>T; p.Q605X) in the second family and a single nucleotide deletion (c.981delG; p.K327<it>fs</it>) in exon 8 of <it>EVC2 </it>gene in the third family. No mutations in the exons, splice sites or the promoter regions of either gene have been found in the index case of the fourth family who exhibited "EvC-like" features.</p> <p>Conclusions</p> <p>Given the small population size of UAE, our data illustrates further the molecular heterogeneity observed in EvC patients and excludes the possibility of a common founder effect for this condition in the UAE reflecting the current ethnic diversity of the country.</p

Diets containing sea cucumber (Isostichopus badionotus) meals are hypocholesterolemic in young rats

Peer reviewedPublisher PD

Infected Cell Killing by HIV-1 Protease Promotes NF-κB Dependent HIV-1 Replication

Acute HIV-1 infection of CD4 T cells often results in apoptotic death of infected cells, yet it is unclear what evolutionary advantage this offers to HIV-1. Given the independent observations that acute T cell HIV-1 infection results in (1) NF-κB activation, (2) caspase 8 dependent apoptosis, and that (3) caspase 8 directly activates NF-κB, we questioned whether these three events might be interrelated. We first show that HIV-1 infected T cell apoptosis, NF-κB activation, and caspase 8 cleavage by HIV-1 protease are coincident. Next we show that HIV-1 protease not only cleaves procaspase 8, producing Casp8p41, but also independently stimulates NF-κB activity. Finally, we demonstrate that the HIV protease cleavage of caspase 8 is necessary for optimal NF-κB activation and that the HIV-1 protease specific cleavage fragment Casp8p41 is sufficient to stimulate HIV-1 replication through NF-κB dependent HIV-LTR activation both in vitro as well as in cells from HIV infected donors. Consequently, the molecular events which promote death of HIV-1 infected T cells function dually to promote HIV-1 replication, thereby favoring the propagation and survival of HIV-1

Expedition 382 Preliminary Report: Iceberg Alley and Subantarctic Ice and Ocean Dynamics

This is the final version. Available from International Ocean Discovery Program via the DOI in this record. International Ocean Discovery Program (IODP) Expedition 382, Iceberg Alley and Subantarctic Ice and Ocean Dynamics, investigated the long-term climate history of Antarctica, seeking to understand how polar ice sheets responded to changes in insolation and atmospheric CO2 in the past and how ice sheet evolution influenced global sea level and vice versa. Five sites (U1534–U1538) were drilled east of the Drake Passage: two sites at 53.2°S at the northern edge of the Scotia Sea and three sites at 57.4°–59.4°S in the southern Scotia Sea. We recovered continuously deposited late Neogene sediment to reconstruct the past history and variability in Antarctic Ice Sheet (AIS) mass loss and associated changes in oceanic and atmospheric circulation. The sites from the southern Scotia Sea (Sites U1536–U1538) will be used to study the Neogene flux of icebergs through “Iceberg Alley,” the main pathway along which icebergs calved from the mar- gin of the AIS travel as they move equatorward into the warmer wa- ters of the Antarctic Circumpolar Current (ACC). In particular, sediments from this area will allow us to assess the magnitude of iceberg flux during key times of AIS evolution, including the following: • The middle Miocene glacial intensification of the East Antarctic Ice Sheet, • The mid-Pliocene warm period, • The late Pliocene glacial expansion of the West Antarctic Ice Sheet, • The mid-Pleistocene transition (MPT), and • The “warm interglacials” and glacial terminations of the last 800 ky. We will use the geochemical provenance of iceberg-rafted detritus and other glacially eroded material to determine regional sources of AIS mass loss. We will also address interhemispheric phasing of ice sheet growth and decay, study the distribution and history of land-based versus marine-based ice sheets around the continent over time, and explore the links between AIS variability and global sea level. By comparing north–south variations across the Scotia Sea be- tween the Pirie Basin (Site U1538) and the Dove Basin (Sites U1536 and U1537), Expedition 382 will also deliver critical information on how climate changes in the Southern Ocean affect ocean circulation through the Drake Passage, meridional overturning in the region, water mass production, ocean–atmosphere CO2 transfer by wind- induced upwelling, sea ice variability, bottom water outflow from the Weddell Sea, Antarctic weathering inputs, and changes in oceanic and atmospheric fronts in the vicinity of the ACC. Comparing changes in dust proxy records between the Scotia Sea and Antarctic ice cores will also provide a detailed reconstruction of changes in the Southern Hemisphere westerlies on millennial and orbital timescales for the last 800 ky. Extending the ocean dust record beyond the last 800 ky will help to evaluate dust-climate couplings since the Pliocene, the potential role of dust in iron fertilization and atmospheric CO2 drawdown during glacials, and whether dust input to Antarctica played a role in the MPT. The principal scientific objective of Subantarctic Front Sites U1534 and U1535 at the northern limit of the Scotia Sea is to recon- struct and understand how ocean circulation and intermediate water formation responds to changes in climate with a special focus on the connectivity between the Atlantic and Pacific basins, the “cold water route.” The Subantarctic Front contourite drift, deposited between 400 and 2000 m water depth on the northern flank of an east–west trending trough off the Chilean continental shelf, is ideally situated to monitor millennial- to orbital-scale variability in the export of Antarctic Intermediate Water beneath the Subantarctic Front. During Expedition 382, we recovered continuously deposited sediments from this drift spanning the late Pleistocene (from ~0.78 Ma to recent) and from the late Pliocene (~3.1–2.6 Ma). These sites are expected to yield a wide array of paleoceanographic records that can be used to interpret past changes in the density structure of the Atlantic sector of the Southern Ocean, track migrations of the Sub- antarctic Front, and give insights into the role and evolution of the cold water route over significant climate episodes, including the following: • The most recent warm interglacials of the late Pleistocene and • The intensification of Northern Hemisphere glaciation.National Science Foundatio

Prevalence of smoking and incidence of initiation in the Latin American adult population: the PLATINO study

Background: the PLATINO project was launched in 2002 in order to study the prevalence of chronic obstructive pulmonary disease (COPD) in Latin America. Because smoking is the main risk factor for COPD, detailed data on it were obtained. the aim of this paper was to evaluate the prevalence of smoking and incidence of initiation among middle-aged and older adults (40 years or older). Special emphasis was given to the association between smoking and schooling.Methods: PLATINO is a multicenter study comprising five cross-sectional population-based surveys of approximately 1,000 individuals per site in São Paulo (Brazil), Santiago (Chile), Mexico City (Mexico), Montevideo (Uruguay) and Caracas (Venezuela). the outcome variable was smoking status (never, former or current). Current smokers were those who reported to smoke within the previous 30 days. Former smokers were those who reported to quit smoking more than 30 days before the survey. Using information on year of birth and age of smoking onset and quitting, a retrospective cohort analysis was carried out. Smoking prevalence at each period was defined as the number of subjects who started to smoke during the period plus those who were already smokers at the beginning of the period, divided by the total number of subjects. Incidence of smoking initiation was calculated as the number of subjects who started to smoke during the period divided by the number of non-smokers at its beginning. the independent variables included were sex, age and schooling.Results: Non-response rates ranged from 11.1% to 26.8%. the prevalence of smoking ranged from 23.9% (95% CI 21.3; 26.6) in São Paulo to 38.5% (95% CI 35.7; 41.2) in Santiago. Males and middle-aged adults were more likely to smoke in all sites. After adjustment for age, schooling was not associated with smoking. Using retrospective cohort analysis, it was possible to detect that the highest prevalence of smoking is found between 20-29 years, while the highest incidence is found between 10-19 years. Age of smoking onset tended to decline over time among females.Conclusion: the prevalence of smoking varied considerably across sites, but was lower among countries with national anti-smoking campaigns.Univ Fed Pelotas, Pelotas, BrazilUniv Republica, Montevideo, UruguayInst Nacl Enfermedades Resp, Mexico City, DF, MexicoUniversidade Federal de São Paulo, São Paulo, BrazilPontificia Univ Catolica Chile, Santiago, ChileCent Univ Venezuela, Caracas, VenezuelaUniversidade Federal de São Paulo, São Paulo, BrazilWeb of Scienc

Ellis-Van Creveld syndrome

Ellis-van Creveld syndrome (EVC) is a chondral and ectodermal dysplasia characterized by short ribs, polydactyly, growth retardation, and ectodermal and heart defects. It is a rare disease with approximately 150 cases reported worldwide. The exact prevalence is unknown, but the syndrome seems more common among the Amish community. Prenatal abnormalities (that may be detected by ultrasound examination) include narrow thorax, shortening of long bones, hexadactyly and cardiac defects. After birth, cardinal features are short stature, short ribs, polydactyly, and dysplastic fingernails and teeth. Heart defects, especially abnormalities of atrial septation, occur in about 60% of cases. Cognitive and motor development is normal. This rare condition is inherited as an autosomal recessive trait with variable expression. Mutations of the EVC1 and EVC2 genes, located in a head to head configuration on chromosome 4p16, have been identified as causative. EVC belongs to the short rib-polydactyly group (SRP) and these SRPs, especially type III (Verma-Naumoff syndrome), are discussed in the prenatal differential diagnosis. Postnatally, the essential differential diagnoses include Jeune dystrophy, McKusick-Kaufman syndrome and Weyers syndrome. The management of EVC is multidisciplinary. Management during the neonatal period is mostly symptomatic, involving treatment of the respiratory distress due to narrow chest and heart failure. Orthopedic follow-up is required to manage the bones deformities. Professional dental care should be considered for management of the oral manifestations. Prognosis is linked to the respiratory difficulties in the first months of life due to thoracic narrowness and possible heart defects. Prognosis of the final body height is difficult to predict