O-mannosyl phosphorylation of alpha-dystroglycan is required for laminin binding.

Alpha-dystroglycan (alpha-DG) is a cell-surface glycoprotein that acts as a receptor for both extracellular matrix proteins containing laminin-G domains and certain arenaviruses. Receptor binding is thought to be mediated by a posttranslational modification, and defective binding with laminin underlies a subclass of congenital muscular dystrophy. Using mass spectrometry- and nuclear magnetic resonance (NMR)-based structural analyses, we identified a phosphorylated O-mannosyl glycan on the mucin-like domain of recombinant alpha-DG, which was required for laminin binding. We demonstrated that patients with muscle-eye-brain disease and Fukuyama congenital muscular dystrophy, as well as mice with myodystrophy, commonly have defects in a postphosphoryl modification of this phosphorylated O-linked mannose, and that this modification is mediated by the like-acetylglucosaminyltransferase (LARGE) protein. These findings expand our understanding of the mechanisms that underlie congenital muscular dystrophy

Comparison of Two Azithromycin Distribution Strategies for Controlling Trachoma in Nepal

OBJECTIVE: The study compares the effectiveness of two strategies for distributing azithromycin in an area with mild-to-moderate active trachoma in Nepal. METHODS: The two strategies investigated were the use of azithromycin for 1) mass treatment of all children, or 2) targeted treatment of only those children who were found to be clinically active, as well as all members of their household. FINDINGS: Mass treatment of children was slightly more effective in terms of decreasing the prevalence of clinically active trachoma (estimated by clinical examination) and of chlamydial infection (estimated by DNA amplification tests), although neither result was statistically significant. CONCLUSION: Both strategies appeared to be effective in reducing the prevalence of clinically active trachoma and infection six months after the treatment. Antibiotic treatment reduced the prevalence of chlamydial infection more than it did the level of clinically active trachoma

A live-attenuated chlamydial vaccine protects against trachoma in nonhuman primates

In cynomolgus macaques, ocular infection with a live trachoma strain lacking the conserved 7.5-kb plasmid induced no ocular pathology but facilitated solid or partial protection from subsequent infection with a virulent strain of trachoma

High body mass index is not associated with atopy in schoolchildren living in rural and urban areas of Ghana

<p>Abstract</p> <p>Background</p> <p>Factors which determine the development of atopy and the observed rural-urban gradient in its prevalence are not fully understood. High body mass index (BMI) has been associated with asthma and potentially atopy in industrialized countries. In developing countries, the transition from rural to urban areas has been associated with lifestyle changes and an increased prevalence of high BMI; however, the effect of high BMI on atopy remains unknown in this population. We therefore investigated the association between high BMI and atopy among schoolchildren living in rural and urban areas of Ghana.</p> <p>Methods</p> <p>Data on skin prick testing, anthropometric, parasitological, demographic and lifestyle information for 1,482 schoolchildren aged 6-15 years was collected. Atopy was defined as sensitization to at least one tested allergen whilst the Centres for Disease Control and Prevention (CDC, Atlanta) growth reference charts were used in defining high BMI as BMI ≥ the 85^thpercentile. Logistic regression was performed to investigate the association between high BMI and atopy whilst adjusting for potential confounding factors.</p> <p>Results</p> <p>The following prevalences were observed for high BMI [Rural: 16%, Urban: 10.8%, p < 0.001] and atopy [Rural: 25.1%, Urban: 17.8%, p < 0.001]. High BMI was not associated with atopy; but an inverse association was observed between underweight and atopy [OR: 0.57, 95% CI: 0.33-0.99]. Significant associations were also observed with male sex [Rural: OR: 1.49, 95% CI: 1.06-2.08; Urban: OR: 1.90, 95% CI: 1.30-2.79], and in the urban site with older age [OR: 1.76, 95% CI: 1.00-3.07], family history of asthma [OR: 1.58, 95% CI: 1.01-2.47] and occupational status of parent [OR: 0.33, 95% CI: 0.12-0.93]; whilst co-infection with intestinal parasites [OR: 2.47, 95% CI: 1.01-6.04] was associated with atopy in the rural site. After multivariate adjustment, male sex, older age and family history of asthma remained significant.</p> <p>Conclusions</p> <p>In Ghanaian schoolchildren, high BMI was not associated with atopy. Further studies are warranted to clarify the relationship between body weight and atopy in children subjected to rapid life-style changes associated with urbanization of their environments.</p

The Natural History of Trachoma Infection and Disease in a Gambian Cohort with Frequent Follow-Up

Trachoma is an infectious disease of the eye that causes blindness in many of the poorest parts of the world. In this paper, we use a novel statistical approach to estimate the characteristics of this disease among people living in The Gambia who were examined every 2 weeks over a 6-month period. We found that the typical duration of infection with Chlamydia trachomatis and of clinically active disease were significantly longer than previously estimated. We tested different hypotheses about the natural history of trachoma that explain the relationship between infection and disease observed in the field. We also confirmed that disease lasts significantly longer among young children under 5 years old compared with older children and adults, even after accounting for high rates of re-infection in this age group, consistent with the development of immunity with age. The long duration of infection, especially among younger children, contributes to the persistence and gradual return of trachoma after community-wide treatment with azithromycin. This implies the need for high treatment coverage if infection is to be eliminated from a community, even where the return of infection after treatment is seen to be slow

Cholesterol-Lowering Drugs and Incident Open-Angle Glaucoma: A Population-Based Cohort Study

Background: Open-angle glaucoma (OAG) is a progressive neurodegenerative disease that may lead to blindness. An elevated intraocular pressure (IOP) is its major risk factor. OAG treatment is currently exclusively directed towards the lowering of the IOP. IOP lowering does not prevent disease progression in all patients and thus other treatment modalities are needed. Earlier studies reported cholesterol-lowering drugs to have neuroprotective properties. The aim of this study was to determine the associations between the use of cholesterol-lowering drugs and incident OAG. Methodology/Principal Findings: Participants in a prospective population-based cohort study underwent ophthalmic examinations, including IOP measurements and perimetry, at baseline and follow-up. The use of statins and non-statin cholesterol-lowering drugs was monitored continuously during the study. Associations between the use of cholesterol-lowering drugs and incident OAG were analyzed with Cox regression; associations between cholesterol-lowering drugs and IOP at follow-up were analyzed with multiple linear regression. During a mean follow-up of 9.8 years, 108 of 3939 eligible participants (2.7%) developed OAG. The hazard ratio for statin use was 0.54 (95% confidence interval 0.31-0.96; P = 0.034) and for non-statin cholesterol-lowering drugs 2.07 (0.81-5.33; P = 0.13). The effect of statins was more pronounced with prolonged use (hazard ratio 0.

Dendritic Spikes Amplify the Synaptic Signal to Enhance Detection of Motion in a Simulation of the Direction-Selective Ganglion Cell

The On-Off direction-selective ganglion cell (DSGC) in mammalian retinas responds most strongly to a stimulus moving in a specific direction. The DSGC initiates spikes in its dendritic tree, which are thought to propagate to the soma with high probability. Both dendritic and somatic spikes in the DSGC display strong directional tuning, whereas somatic PSPs (postsynaptic potentials) are only weakly directional, indicating that spike generation includes marked enhancement of the directional signal. We used a realistic computational model based on anatomical and physiological measurements to determine the source of the enhancement. Our results indicate that the DSGC dendritic tree is partitioned into separate electrotonic regions, each summing its local excitatory and inhibitory synaptic inputs to initiate spikes. Within each local region the local spike threshold nonlinearly amplifies the preferred response over the null response on the basis of PSP amplitude. Using inhibitory conductances previously measured in DSGCs, the simulation results showed that inhibition is only sufficient to prevent spike initiation and cannot affect spike propagation. Therefore, inhibition will only act locally within the dendritic arbor. We identified the role of three mechanisms that generate directional selectivity (DS) in the local dendritic regions. First, a mechanism for DS intrinsic to the dendritic structure of the DSGC enhances DS on the null side of the cell's dendritic tree and weakens it on the preferred side. Second, spatially offset postsynaptic inhibition generates robust DS in the isolated dendritic tips but weak DS near the soma. Third, presynaptic DS is apparently necessary because it is more robust across the dendritic tree. The pre- and postsynaptic mechanisms together can overcome the local intrinsic DS. These local dendritic mechanisms can perform independent nonlinear computations to make a decision, and there could be analogous mechanisms within cortical circuitry

Concentration-Dependent Modulation of Amyloid-␤ in Vivo and in Vitro Using the ␥-Secretase Inhibitor, LY-450139

ABSTRACT LY-450139 is a ␥-secretase inhibitor shown to have efficacy in multiple cellular and animal models. Paradoxically, robust elevations of plasma amyloid-␤ (A␤) have been reported in dogs and humans after administration of subefficacious doses. The present study sought to further evaluate A␤ responses to LY-450139 in the guinea pig, a nontransgenic model that has an A␤ sequence identical to that of human. Male guinea pigs were treated with LY-450139 (0.2-60 mg/kg), and brain, cerebrospinal fluid, and plasma A␤ levels were characterized at 1, 3, 6, 9, and 14 h postdose. Low doses significantly elevated plasma A␤ levels at early time points, with return to baseline within hours. Higher doses inhibited A␤ levels in all compartments at early time points, but elevated plasma A␤ levels at later time points. To determine whether this phenomenon occurs under steadystate drug exposure, guinea pigs were implanted with subcutaneous minipumps delivering LY-450139 (0.3-30 mg/kg/day) for 5 days. Plasma A␤ was significantly inhibited at 10 -30 mg/kg/day, but significantly elevated at 1 mg/kg/day. To further understand the mechanism of A␤ elevation by LY-450139, H4 cells overexpressing the Swedish mutant of amyloid-precursor protein and a mouse embryonic stem cell-derived neuronal cell line were studied. In both cellular models, elevated levels of secreted A␤ were observed at subefficacious concentrations, whereas dose-responsive inhibition was observed at higher concentrations. These results suggest that LY-450139 modulates the ␥-secretase complex, eliciting A␤ lowering at high concentrations but A␤ elevation at low concentrations. The pathological accumulation of amyloid-␤ peptide into dense core plaques in the brains of Alzheimer&apos;s disease patients is the ultimate target of multiple disease-modifying drug discovery efforts. One strategy that has entered the clinic is the use of a ␥-secretase inhibitor to reduce central A␤ production. Preclinically, multiple ␥-secretase inhibitors have demonstrated central and peripheral A␤-lowering activity in transgenic mouse lines overexpressing human mutant amyloid precursor protein The ability of plasma and CSF A␤ to track pharmacological changes in brain A␤ provides a useful method for tracking the efficacy of ␥-secretase inhibitors in the clinic. Because each compartment may have varying degrees of drug exposure and different clearance rates for both drug and A␤, it is important to understand the dynamics of A␤ in each compartment. Dose-response and time course studies with ␥-secretase inhibitors in transgenic mice have revealed difArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.110700. ABBREVIATIONS