The first missense alteration in the MCPH1 gene causes autosomal recessive microcephaly with an extremely mild cellular and clinical phenotype

Autosomal recessive primary microcephaly (MCPH) is a rare neurodevelopmental disorder characterized by mental retardation and congenital microcephaly with a head circumference at least 4 SD below age and sex means, in the absence of other significant malformations or neurological deficits. Truncating alterations in the MCPH1 gene have previously been shown to exhibit a distinct cellular phenotype, with a high proportion of prophase-like cells (>10%) due to premature chromosome condensation in early G2- and delayed decondensation in early G1-phase of the cell cycle. We report here the first patient with a homozygous substitution of a highly conserved threonine residue by an arginine (c.80C>G, Thr27Arg) localized in the N-terminal BRCT domain of MCPH1. The cellular and clinical phenotype of this patient is much less pronounced than that of previously described patients with truncating alterations in the MCPH1 gene. Firstly, the fraction of prophase-like cells accounts for just 3-4% of the cell population. Secondly, clinically, he has only a very mild mental retardation with predominantly delayed motor skills but normal verbal IQ attainment. Additionally, head circumference was less severely affected, being -2.4 SD at birth and -3 SD at the age of six years. This justifies reconsideration and widening of the clinical phenotype definition of MCPH1.     

Brain-immune interactions and disease susceptibility

Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases. This review focuses on the regulation of the immune system via the neuroendocrine system, and underlines the link between neuroendocrine dysregulation and development of major depressive disorders, autoimmune diseases and osteoporosis.     

The effect of correct and consistent condom use on chlamydial and gonococcal infection among urban adolescents

OBJECTIVE: To evaluate the relationship between self-reported correct and consistent condom use and chlamydial and gonococcal infection. DESIGN: Cross-sectional study. SETTING: An urban adolescent health care clinic.Patients A total of 509 adolescent girls tested for Chlamydia trachomatis and Neisseria gonorrhoeae infection by urine nucleic acid amplification tests.Main Outcome Measure Effect of condom use on infection rates of chlamydia and gonorrhea. Consistent condom use was defined as using condoms for every act of vaginal sex and correct use as consistent use without any of the following: beginning sex without a condom, taking it off before finishing sex, flipping it over, condom breakage, or condom slippage. RESULTS: A total of 95% of the participants were African American, with a mean age of 16.6 years. Chlamydia prevalence was 21% (105/509) and gonorrhea prevalence was 7% (36/509). Condom errors were reported by 316 (71%) of 442 participants who had reported using a condom at least once in the previous 3 months. Consistent use was reported by 176 patients (35%); however, both correct and consistent use was reported by only 80 patients (16%). After adjusting for confounders, correct and consistent use was protective for chlamydia (odds ratio, 0.4; 95% confidence interval, 0.2-1.0) and highly protective for gonorrhea (odds ratio, 0.1; 95% confidence interval, 0-0.7). CONCLUSION: Our findings indicate that assessing both correctness and consistency of use is important for evaluation of condom effectiveness.     

Anthrax lethal toxin represses glucocorticoid receptor (GR) transactivation by inhibiting GR-DNA binding in vivo

Anthrax lethal factor (LF) is a non-competitive repressor of glucocorticoid (GR) and progesterone receptor (PR) transactivation. This repression was shown to be specific and selective and was dependent on promoter context and receptor subtype. Anthrax lethal toxin (LeTx) selectively repressed GR-mediated transactivation but not transrepression. The DNA binding region of GR was required for repression by LeTx and LeTx prevented GR-DNA binding in vivo, which had downstream consequences on polymerase II binding and histone acetylation. In addition, LeTx also prevented the accessory protein C/EBP from binding to a GR-responsive promoter. We hypothesize that LeTx may remove/inactivate one of the many co-factors or accessory proteins that are required to stabilize the GR-DNA complex. These findings enhance the current knowledge of the molecular mechanism by which the anthrax lethal factor represses nuclear hormone receptors and could provide an approach to overcome some of LeTx's effects.     

Expression of human intestinal mucin is modulated by the beta-galactoside binding protein galectin-3 in colon cancer

BACKGROUND & AIMS: Alterations in the production of the beta-galactoside binding protein galectin-3 and of MUC2 intestinal mucin have been independently correlated with the malignant behavior of human colon cancer cells. MUC2 mucin is a major ligand for galectin-3, and colon cancer cells that differ quantitatively in MUC2 expression may also vary in expression of galectin-3. The current study was designed to investigate the relationship between galectin-3 production and MUC2 mucin synthesis by human colon cancer cells. METHODS: The effect of galectin-3 on MUC2 mucin production was assessed by stable transfection of sense and antisense galectin-3 expression constructs under the control of constitutive or tetracycline-inducible promoters into human colon cancer cells. Galectin-3 and MUC2 expression were determined by fluorescence-activated cell sorter (cell surface galectin-3), Western and Northern analysis (galectin-3, MUC2), and gel filtration of secreted high-weight glycoprotein (MUC2). In vitro results were confirmed in vivo by analysis of cecal xenografts in athymic mice. RESULTS: Colon cancer cells with high levels of galectin-3 also had high levels of MUC2 mucin, whereas those with low galectin-3 levels had low MUC2 levels. Alterations in galectin-3 levels by expression of sense or antisense galectin-3 constructs resulted in parallel alterations of MUC2 protein and RNA. Induction of antisense to galectin-3 in vivo was associated with decreases in both galectin-3 and MUC2 protein in cecal xenografts. CONCLUSIONS: The beta-galactoside binding protein galectin-3 modulates the expression of its major ligand MUC2 mucin in human colon cancer cells. This may have important implications for understanding the role of galectin-3 in colon cancer metastasis.     

Crohn disease in patients with familial Mediterranean fever

Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 +/- 10.0 yr versus 26.2 +/- 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.     

Clinicopathologic study after submacular removal of choroidal neovascular membranes treated with verteporfin ocular photodynamic therapy

PURPOSE: To report the clinicopathologic findings after submacular removal of choroidal neovascular membranes (CNV) treated with verteporfin ocular photodynamic therapy. DESIGN: Interventional case series. METHODS: Retrospective review of eight eyes of eight patients who underwent submacular surgery for CNV after having previously received verteporfin ocular photodynamic therapy for presumed ocular histoplasmosis (one patient), age-related macular degeneration ([AMD] three patients) pathologic myopia (two patients), punctate inner choroiditis (one patient), and idiopathic CNV (one patient). All cases had undergone ocular photodynamic therapy with verteporfin using standard protocols. Six of eight patients suffered a submacular hemorrhage after ocular photodynamic therapy, and two of eight patients refused further ocular photodynamic therapy. All patients subsequently had submacular surgery with removal of the CNV. One membrane was routinely processed, sectioned, and stained with hematoxylin and eosin. Five membranes were stained with toluidine blue for light microscopic examination. Semithin (1.0 microm) sections were cut and stained with uranyl acetate-lead citrate for transmission electron microscopy. RESULTS: Choroidal neovascular membranes were removed at 3 days (presumed ocular histoplasmosis), 29 days (punctate inner choroiditis), 63 days (AMD, pathologic myopia), 66 days (AMD), 107 days (pathologic myopia), 116 days (AMD), and 152 days (idiopathic) after verteporfin ocular photodynamic therapy. Histopathologic and ultrastructural examination showed areas of vascular occlusion at 3 days that were not seen at later time points. All specimens had patent CNV. There were signs of vascular damage with extravasated erythrocytes and fibrin, pigment clumping in cells, and inflammatory cells in all but the 3-day specimen.CONCLUSIONS: This case series presents data only from patients who refused repeat treatment with ocular photodynamic therapy or who developed submacular hemorrhage after initial photodynamic therapy. Histopathologic evaluation of CNV 3 days after verteporfin ocular photodynamic therapy showed partial vascular occlusion that was not present in later specimens. These later specimens demonstrated evidence of vascular damage. Verteporfin ocular photodynamic therapy does not appear to lead to permanent and complete occlusion of the CNV. Thus, treatments that lead to permanent closure of CNV without damage to the retinal pigment epithelium and sensory retina are still needed.     

The prognostic significance of a system for classifying mechanical injuries of the eye (globe) in open-globe injuries

PURPOSE: The aim of this study was to determine the prognostic significance of a previously published system for classifying mechanical injuries of the eye (globe) in open-globe injuries. METHODS: The medical records of 150 patients with open-globe injuries identified from an established institutional database were retrospectively reviewed to classify all injuries at presentation by the four specific variables of the classification system: type of injury, defined by the mechanism of injury; grade of injury, defined by visual acuity in the injured eye at initial examination; pupil, defined as the presence or absence of a relative afferent pupillary defect in the injured eye; and zone of injury, defined by the location of the eye-wall opening. Final visual outcomes for these injuries were also recorded. Logistic regression models were used to analyze the data and to determine whether relationships existed between the specific classification variables and final visual acuity in the injured eyes. RESULTS: All four classification variables were significant predictors of visual outcome. When adjusted for the other variables, grade and pupil were the most significant predictors of final visual acuity. CONCLUSION: This system for classifying mechanical injuries of the eye appears to be prognostic for visual outcomes in open-globe injuries. In particular, the measurement of visual acuity and testing for a relative afferent pupillary defect at the initial examination should be performed in all injured eyes because of their relative prognostic significance.