Williams syndrome: a relationship between genetics, brain morphology and behaviour.

BACKGROUND: Genetically Williams syndrome (WS) promises to provide essential insight into the pathophysiology of cortical development because its ∼28 deleted genes are crucial for cortical neuronal migration and maturation. Phenotypically, WS is one of the most puzzling childhood neurodevelopmental disorders affecting most intellectual deficiencies (i.e. low-moderate intelligence quotient, visuospatial deficits) yet relatively preserving what is uniquely human (i.e. language and social-emotional cognition). Therefore, WS provides a privileged setting for investigating the relationship between genes, brain and the consequent complex human behaviour. METHODS: We used in vivo anatomical magnetic resonance imaging analysing cortical surface-based morphometry, (i.e. surface area, cortical volume, cortical thickness, gyrification index) and cortical complexity, which is of particular relevance to the WS genotype-phenotype relationship in 22 children (2.27-14.6 years) to compare whole hemisphere and lobar surface-based morphometry between WS (n = 10) and gender/age matched normal controls healthy controls (n = 12). RESULTS: Compared to healthy controls, WS children had a (1) relatively preserved Cth; (2) significantly reduced SA and CV; (3) significantly increased GI mostly in the parietal lobe; and (4) decreased CC specifically in the frontal and parietal lobes. CONCLUSION: Our findings are then discussed with reference to the Rakic radial-unit hypothesis of cortical development, arguing that WS gene deletions may spare Cth yet affecting the number of founder cells/columns/radial units, hence decreasing the SA and CV. In essence, cortical brain structure in WS may be shaped by gene-dosage abnormalities.

Dietary intake of Sudanese women: a comparative assessment of nutrient intake of displaced and non-displaced women.

OBJECTIVES: To determine the daily intake of essential micro- and macronutrients in Sudanese women, with specific focus on dietary fat and essential fatty acids, and compare the dietary intakes of internally displaced women with those of the non-displaced population. METHODS: Dietary intakes of displaced southern (n=44) and non-displaced southern (n=30) and northern (n=39) Sudanese women were obtained by single 24-hour recall method, and daily nutrient intakes were calculated using 'Foodbase' nutritional software. The displaced women were recruited from Mayo and Soba Aradi camps, south of Khartoum city; and non-displaced southern and northern Sudanese women were recruited from antenatal clinics, universities, hospitals and the community in Khartoum city and Omdurman, Sudan. RESULTS: Carbohydrates provided over 60% of dietary energy for all the Sudanese women groups. The displaced women had significantly lower intake of energy (1744 ± 344 kcal/d), starch (p<0.001) and carbohydrates (312 ± 11 g/d, p<0.01) than both non-displaced southern (1972 ± 229 kcal/d energy, 358 ± 56 g/d carbohydrates) and northern Sudanese women (1988 ± 226 kcal/d energy, 357 ± 56g/d carbohydrates). Fat intake was also lower in the displaced group (34.1 ± 11.9 g/d) than in the non-displaced counterpart (38.5 ± 10.2 g/d) (p<0.05), but was not significantly different from northern Sudanese women (37.6 ± 10.6, p>0.05). Intakes of iodine (33.60-56.96 µg/d), zinc (7.12-9.92 mg/d), retinol (226.1-349.7 µg/d), riboflavin (0.44-0.70 mg/d) and docosahexaenoic acid (11.70-33.49 mg/d) amongst Sudanese women were very low compared with recommendations. CONCLUSION: The Sudanese diet was less diverse and differences in energy and nutrients intakes between groups were due to the amounts of food consumed. This view is supported by a lack of significant differences when intakes were expressed as proportion of whole energy between all groups of women.

Milk of northern Sudanese mothers whose traditional diet is high in carbohydrate contains low docosahexaenoic acid.

AIM: The suckling neonates and infants are reliant primarily on the mother for optimal supply of docosahexaenoic acid (DHA). The richest source of preformed DHA is cold-water oily fish. Although there is paucity of data, existing evidence suggest women with restricted access to these foods have low or marginal DHA status. The aim of the study was to investigate milk fatty acids of Sudanese mothers whose traditional diet is high in carbohydrate and low in fat and gain some insight into the provision of DHA to the suckling offspring. METHODS: Colostrum (n =26), transitional (n=20) and mature (n=14) milk samples were obtained from Northern Sudanese women (NSW) recruited prior to delivery from Ibrahim Malik and Khartoum Teaching Hospitals. RESULTS: The arachidonic acid content of the colostrum (0.87±0.28%) and transitional (0.89± 0.29%) and mature (0.48±0.12%) milk of the NSW were broadly comparable with published international values. In contrast, the DHA level (colostrum 0.13±0.07%, transitional 0.13±0.06% and mature milk 0.06±0.05%) was very low. CONCLUSION: The study reveals breast milk of NSW, whose traditional diet is almost devoid of fish and fish products, is unlikely to provide sufficient DHA to support optimal postnatal neuro-visual development.

Electron microscopic study on the development of precapsular layer in eyes with exfoliation syndrome.

PURPOSE: To search for a pathogenic mechanism for the formation of the precapsular layer on the anterior lens surface in pre-exfoliative eyes. METHODS: We examined anterior lens capsules obtained during surgery from 38 patients (control, 16; exfoliation suspect, 10; exfoliation, 12) by transmission electron microscopy. RESULTS: A precapsular layer was found in 5 of 16 controls and 7 of 10 exfoliation suspects. It was composed mainly of microfibrils 5-8 nm in diameter. Degenerated zonular fragments were occasionally found interspersed in, and sometimes merged with microfibrils of the precapsular layer. CONCLUSION: Zonular fibers might contribute to the formation of the precapsular layer in pre-exfoliation stages.

Comparative study of retinal nerve fiber layer damage in Japanese patients with normal- and high-tension glaucoma.

PURPOSE: To look for possible differences in the pattern of retinal nerve fiber layer (RNFL) damage induced by normal- and high-tension glaucoma. METHODS: The study included randomly selected eyes from 27 patients with open-angle, high-tension glaucoma (mean age, 54.7 +/- 15.0 years; range 21-74 years) and from 19 age-matched patients with normal-tension glaucoma (mean age, 55.7 +/- 11.9 years; range 35-83 years). Eyes were examined using scanning laser polarimetry. RESULTS: The ratio between the superior and inferior quadrant thickness, or symmetry, was significantly lower in patients with high-tension glaucoma (1.00 +/- 0.22) than in patients with normal-tension glaucoma (1.18 +/- 0.32). Similarly, the ratio of the superior to the nasal quadrant thickness was significantly lower in patients with high-tension glaucoma (1.56 +/- 0.38) than in patients with normal-tension glaucoma (1.80 +/- 0.29). No statistically significant differences in the other parameters were detected between the two groups. CONCLUSION: These results show that the pattern of RNFL change is different in patients with high- and low-tension glaucoma. The thickness of the RNFL is reduced symmetrically in the superior and inferior quadrants in high-tension glaucoma, whereas a more localized defect on the inferior RNFL occurs in normal-tension glaucoma.

Role of NF-kappaB-mediated interleukin-8 expression in intraocular neovascularization.

PURPOSE: To investigate the role of interleukin (IL)-8 in intraocular neovascularization and the mechanism of its production. METHODS: Interleukin-8 was measured with enzyme-linked immunosorbent assays in vitreous and aqueous fluid obtained from patients with neovascular diseases. Localization of IL-8 was examined by immunohistochemistry. An in vitro angiogenesis assay was performed on collagen gels, by using bovine aortic endothelial cells to determine the effect of the vitreous fluid. In bovine retinal glial cells under hypoxia, NF-kappaB activation was evaluated by immunoblot analysis and by electrophoretic mobility shift assay, and IL-8 and vascular endothelial growth factor (VEGF) mRNA expression was determined by semiquantitative reverse transcription-polymerase chain reaction. RESULTS: The concentration of IL-8 in vitreous fluid of patients with retinal neovascularization was significantly higher than that of patients without neovascular disease. Interleukin-8 immunostaining was detected in vascular endothelial cells and glial cells in the retinas with neovascularization. Vitreous fluid with high concentrations of IL-8 induced tubular morphogenesis in endothelial cells, and this effect was inhibited to a similar extent by neutralizing antibodies to IL-8 or to VEGF. In glial cells, in vitro, hypoxia induced NF-kappaB activation and increased IL-8 and VEGF mRNA. Furthermore, pyrrolidine dithiocarbamate, a specific inhibitor of NF-kappaB activation, prevented the induction of the IL-8 gene, but not that of the VEGF gene. CONCLUSIONS: These results suggest that IL-8 induced by hypoxia and mediated by NF-kappaB may contribute to the pathogenesis of intraocular neovascularization.

The role of NF-kappaB in retinal neovascularization in the rat. Possible involvement of cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 family.

Hypoxia precedes neovascularization in many retinal diseases that can lead to irreversible vision loss. The transcription factor NF-kappaB is activated by hypoxia and regulates the expression of many genes, including angiogenic factors. The relation between the NF-kappaB activation and the cytokine-induced neutrophil chemoattractant (CINC), a member of the interleukin-8 (IL-8) family, was investigated by immunohistochemistry in a rat model of proliferative retinopathy presumably caused by relative hypoxia. Activated NF-kappaB and CINC immunoreactivity was detected in retinal glial cells in the nonperfused retina and in neovascular cells. Activated NF-kappaB was detected before the CINC staining, and both of these events occurred before the development of neovascularization. The intensity of both activated NF-kappaB and CINC staining remained increased during the development of neovascularization and then declined as neovascularization regressed. In rat retinal glial cells in vitro, dexamethasone, an inhibitor of NF-kappaB activation, prevented the hypoxia-induced increase in the amount of CINC mRNA. Furthermore, CINC induced neovascularization in a rat corneal pocket model. These results suggest that hypoxia-induced activation of NF-kappaB results in CINC production and participates in the induction of retinal neovascularization.

Early changes in iris blood vessels in exfoliation syndrome.

PURPOSE: To look for possible changes in iris blood vessels that might precede the formation of true exfoliation material, and to correlate these changes, if present, to aging of the iris. METHODS: Iris blood vessels of 10 clinically normal irises from 10 eyes (ages: 1 day-80 years), 4 irises with exfoliation (ages: 64-80 years) and 3 irises from primary open-angle glaucoma (POAG) (ages: 27-65 years) were examined with an electron microscope. RESULTS: Pronounced multilayering of the basal lamina around the vessels, abnormal excessive formation of microfibrils, presence of atrophic invaginations in the outer cell membranes of endothelial cells containing interlacing basal lamina, and an apparent decrease in the perivascular collagen fibers were evident in exfoliative iris vessels devoid of true exfoliation material. Similar, but much milder, changes were evident in normal aged and POAG irises. CONCLUSIONS: Abnormal elastic tissue and/or basal lamina production plays a role early in the formation of exfoliation material around iris blood vessels.

Ultrastructural age-related changes on the posterior iris surface. A possible relationship to the pathogenesis of exfoliation.

OBJECTIVES: To verify the presence of age-related changes in the human iris and to determine whether such changes could be related to the pathogenesis of the exfoliation syndrome. DESIGN: Ultrastructural examination of the posterior surface of the normal iris in 9 enucleated eyes. PATIENTS OR OTHER PARTICIPANTS: Eyes of persons aged 1 day, 3 months, and 3, 9, 27, 52, 59, 59, and 65 years. MAIN OUTCOME MEASURE: The presence of aging changes in the iris. RESULTS: Aging changes included duplication of the basal lamina of posterior iris pigment epithelial cells, formation of atrophic invaginations in the posterior cell membranes containing interlacing basal lamina, formation (or deposition) of microfibrils 11 to 13 nm in diameter, with a banding periodicity of 12 to 16 nm, deposition of electron-dense material in relation to the basal lamina and/or microfibrils, and the presence of some fine granular material overlying the basal lamina. CONCLUSION: These changes have been consistently described before in association with exfoliation material, which suggests the possibility that exfoliation is an eventual aging process.