Causes of blindness among students in blind school institutions in a developing country.

Out of 270 students in 17 blind school institutions in Malawi 73 per cent were blind before the age of three. The most common cause for the blindness was ocular infection (75-2 per cent). Meales, as a single cause, was responsible for 43-7 per cent of the cases and smallpox for 5-2 per cent. Bacterial infections were incriminated in 26-3 per cent of the cases. Most of these had received traditional medicine during the acute phase of the disease. Hereditary factors as causes of blindness were found in 7-8 per cent of the cases. These included congenital cataracts (2-6 per cent), optic atorphy of unknown origin (3-0 per cent), microphthalmos (1-5 per cent), and macular degeneration (0-7 per cent). Careful ophthalmological examination showed that in 37 cases an intervention could be attempted in order to improve the vision. In the 11 most favourable cases this was attempted, with the result that nine cases gained a useful vision of 4/60 to 6/18 in the better eye.     

Immunohistochemistry and electron microscopy of choroidal infiltrates and Dalen-Fuchs nodules in sympathetic ophthalmia

An immunohistological study using monoclonal antibodies directed at specific membrane antigens of various inflammatory cells was carried out in order to evaluate the identity and topographic localization of the immuno-competent cells in an enucleated eye from a 6-year-old black patient with a three-month history of sympathetic ophthalmia. Correlative light and transmission electron microscopic examination of serial sections was also performed. The data demonstrated that the predominant cells within the choroidal infiltrate were T-lymphocytes (Leu 1+). T-cell subset analysis disclosed that most of these cells harbored specific antigenic determinants of the helper phenotype (Leu 3a+). A smaller proportion of the T cells demonstrated the specific determinants of the suppressor subtype (Leu 2a+). The helper/suppressor ratio varied slightly and ranged in most areas of the choroid between 3:1 and 4:1. Additionally, approximately 15% of the infiltrating lymphocytes harbored the Leu 14+ determinant specific for B cells. The latter were located in the outer choroid adjacent to the sclera. Very few natural killer (NK) cells (Leu 7+) were identified throughout the choroid. The granulomatous foci in the choroid were composed mainly of epithelioid cells and histiocytes expressing the OKM1+ and M221+ antigenic determinants on their membranes and demonstrating a high cytoplasmic nonspecific esterase activity (ANAE+). Within the Dalen-Fuchs nodules, similar to the choroidal nodules, there was a predominance of histiocytes and epithelioid cells (OKM1+, M221+, ANAE+), a few T-helper cells (Leu 1+, Leu3a+) and some OKM1-, M221- cells whose origin could not be determined. These findings were corroborated by electron microscopic observations of serial sections. Careful light and electron microscopic studies disclosed breaks in Bruch's membrane underlying some of Dalen-Fuchs nodules. In our opinion, these observations may be interpreted as the demonstration that Dalen-Fuchs' nodules and the choroidal granulomatous foci could be formed by identical cells of similar function and origin.     

Oncogenes and Angiogenesis: down-regulation of thrombospondin-1 in normal fibroblasts exposed to factors from cancer cells harboring mutant ras

The onset of angiogenesis in cancer often involves down-regulation of endogenous angiogenesis inhibitors, of which thrombospondin-1 (TSP-1) is a paradigm. As this effect is thought to occur under the influence of transforming genetic lesions (e.g., expression of the mutant ras oncogene), its nature is regarded as intrinsic to cancer cells themselves. Here, we show that ras-transformed cancer cells can also induce TSP-1 down-regulation in their adjacent nontransformed stromal fibroblasts, but not in endothelial cells, in a paracrine and distance-dependent manner. Indeed, several H-ras-expressing fibrosarcoma (528ras1, B6ras, and NIH3T3Ras) and carcinoma (DLD-1 and IEC18Ras3) cells were found to release soluble factors capable of suppressing TSP-1 protein, mRNA, and promoter activity in nontumorigenic, immortalized dermal fibroblastic cell lines in culture (e.g., in fibroblasts expressing enhanced green fluorescent protein/TSP-1 reporter). This effect was abrogated in Id1-/- fibroblasts. At least two low molecular weight (<3 kDa), heat-labile, and trypsin-resistant mediators of TSP-1 suppression were found to be released from 528ras1 cells. Their effects on normal fibroblasts were inhibited (albeit to different extents) by pertussis toxin and, in one case, by dimethylsphingosine, none of which affected TSP-1 expression by 528ras1 cells. Collectively, our study suggests that the effect of mutant ras on tumor neovascularization is not limited to changes in angiogenic properties of cancer cells themselves. Rather, mutant ras, through a different signaling mechanism, may modulate the properties of the adjacent normal stroma, thus eliciting a proangiogenic field effect.     

Embryonic stem cells prevent developmental cardiac defects in mice

The potential therapeutic use of embryonic stem cells (ESCs) has gathered the attention of the scientific and medical communities recently. We report that in addition to their unique capacity to populate defective cardiac tissues, ESCs secrete factors that correct gene expression profiles in the defective neighboring cells. Id (inhibitor of DNA binding) gene knockout (KO) mouse embryos die at midgestation because of multiple cardiac defects, but injection of ESCs into preimplantation Id KO embryos prevents these defects and corrects gene expression profiles throughout the heart. ESCs injected into expectant mothers only partially rescue cardiac defects in the Id KO embryos. Two secreted factors are implicated in the rescue process: insulin-like growth factor I accounts for the long-range action of the ESCs, and Wnt5a, a short-range factor, corrects gene expression profiles in the Id KO hearts. Future studies are discussed.     

Population history and infrequent mutations: how old is a rare mutation? GUCY2D as a worked example

The mosaic pattern of haplotypes observed around a single mutation results from one or several founder events. The difficulties involved in calculating the age of the variant are greatly reduced by assuming a single event, but this simplification may bias analysis of the genealogy of the mutation. However, if it is assumed that more than one founder event occurred, the number of genealogies is very large and the likelihood of every possible tree could not be realistically calculated. A multipoint approach is required, given the number of independent variables needed to describe a complex bifurcating genealogy. Starting from the observation that a limited number of parameters is needed for calculation of the simplest models of bifurcating genealogies, we show that the probability density of a two-ancestor model genealogy can be simply described as an algebraic function in a closed form, two coalescence times being calculated simultaneously without compromising accuracy. Implementation in a Bayesian framework is facilitated by the simplicity of the function, which describes the reciprocal relationship between the region of complete linkage disequilibrium and the branch length of the tree. We illustrate the use of haplotype information about allele-sharing decay around a mutation as a genetic clock, using data for two GUCY2D mutations in Mediterranean populations.     

Multimodal silica nanoparticles are effective cancer-targeted probes in a model of human melanoma

Nanoparticle-based materials, such as drug delivery vehicles and diagnostic probes, currently under evaluation in oncology clinical trials are largely not tumor selective. To be clinically successful, the next generation of nanoparticle agents should be tumor selective, nontoxic, and exhibit favorable targeting and clearance profiles. Developing probes meeting these criteria is challenging, requiring comprehensive in vivo evaluations. Here, we describe our full characterization of an approximately 7-nm diameter multimodal silica nanoparticle, exhibiting what we believe to be a unique combination of structural, optical, and biological properties. This ultrasmall cancer-selective silica particle was recently approved for a first-in-human clinical trial. Optimized for efficient renal clearance, it concurrently achieved specific tumor targeting. Dye-encapsulating particles, surface functionalized with cyclic arginine-glycine-aspartic acid peptide ligands and radioiodine, exhibited high-affinity/avidity binding, favorable tumor-to-blood residence time ratios, and enhanced tumor-selective accumulation in αvβ3 integrin-expressing melanoma xenografts in mice. Further, the sensitive, real-time detection and imaging of lymphatic drainage patterns, particle clearance rates, nodal metastases, and differential tumor burden in a large-animal model of melanoma highlighted the distinct potential advantage of this multimodal platform for staging metastatic disease in the clinical setting.     

Cancer cells preferentially lose small chromosomes

Genetic and genomic aberrations are the primary cause of cancer. Chromosome missegregation leads to aneuploidy and provides cancer cells with a mechanism to lose tumor suppressor loci and gain extra copies of oncogenes. Using cytogenetic and array‐based comparative genomic hybridization data, we analyzed numerical chromosome aneuploidy in 43,205 human tumors and found that 68% of solid tumors are aneuploid. In solid tumors, almost all chromosomes are more frequently lost than gained with chromosomes 7, 12 and 20 being the only exceptions with more frequent gains. Strikingly, small chromosomes are lost more readily than large ones, but no such inverse size correlation is observed with chromosome gains. Because of increasing levels of proteotoxic stress, chromosome gains have been shown to slow cell proliferation in a manner proportional to the number of extra gene copies gained. However, we find that the extra chromosome in trisomic tumors does not preferentially have a low gene copy number, suggesting that a proteotoxicity‐mediated proliferation barrier is not sustained during tumor progression. Paradoxically, despite a bias toward chromosome loss, gains of chromosomes are a poor prognostic marker in ovarian adenocarcinomas. In addition, we find that solid and non‐solid cancers have markedly distinct whole‐chromosome aneuploidy signatures, which may underlie their fundamentally different etiologies. Finally, preferential chromosome loss is observed in both early and late stages of astrocytoma. Our results open up new avenues of enquiry into the role and nature of whole‐chromosome aneuploidy in human tumors and will redirect modeling and genetic targeting efforts in patients.