Defective N-sulfation of heparan sulfate proteoglycans limits PDGF-BB binding and pericyte recruitment in vascular development

During vascular development, endothelial platelet-derived growth factor B (PDGF-B) is critical for pericyte recruitment. Deletion of the conserved C-terminal heparin-binding motif impairs PDGF-BB retention and pericyte recruitment in vivo, suggesting a potential role for heparan sulfate (HS) in PDGF-BB function during vascular development. We studied the participation of HS chains in pericyte recruitment using two mouse models with altered HS biosynthesis. Reduction of N-sulfation due to deficiency in N-deacetylase/N-sulfotransferase-1 attenuated PDGF-BB binding in vitro, and led to pericyte detachment and delayed pericyte migration in vivo. Reduced N-sulfation also impaired PDGF-BB signaling and directed cell migration, but not proliferation. In contrast, HS from glucuronyl C5-epimerase mutants, which is extensively N- and 6-O-sulfated, but lacks 2-O-sulfated L-iduronic acid residues, retained PDGF-BB in vitro, and pericyte recruitment in vivo was only transiently delayed. These observations were supported by in vitro characterization of the structural features in HS important for PDGF-BB binding. We conclude that pericyte recruitment requires HS with sufficiently extended and appropriately spaced N-sulfated domains to retain PDGF-BB and activate PDGF receptor beta (PDGFRbeta) signaling, whereas the detailed sequence of monosaccharide and sulfate residues does not appear to be important for this interaction.     

Three-year visual and anatomic results of administrating intravitreal bevacizumab in inflammatory ocular neovascularization

ObjectiveTo assess the 3-year visual outcome of intravitreal bevacizumab in inflammatory ocular neovascularization.DesignExperimental study.MethodsRetrospective multicenter consecutive case series in 81 patients with inflammatory ocular neovascularization refractory to standard therapy and treated with intravitreal bevacizumab. The outcome measures included improvement of best corrected visual acuity expressed as logarithm of minimum angle of resolution (logMAR) and paired comparison decrease in central foveal thickness by optical coherence tomography.ResultsMean best corrected visual acuity improved from baseline 0.699 (6/30 or 20/101) (SD 0.434) to 0.426 (6/16 or 20/53) (SD 0.428) (n = 81; p < 0.001), a gain of 2.7 lines (median 3 injections; 81 eyes; 81 patients). Paired comparisons revealed significant central foveal flattening at 3 years of 97.9 μm (n = 51; p < 0.001). In a subgroup analysis, visual improvement was significant for ocular histoplasmosis (p = 0.026); multifocal choroiditis (p = 0.05); serpiginous choroiditis (p = 0.028); ocular toxoplasmosis (p = 0.042); and punctate inner choroidopathy (p = 0.015). In a subgroup analysis, foveal flattening was significant for ocular histoplasmosis (p = 0.004); multifocal choroiditis (p = 0.007); serpiginous choroiditis (p = 0.011); and punctate inner choroidopathy (p = 0.001). Of the group, 5 eyes developed submacular fibrosis, 1 eye retinal pigment epithelial tear, and 1 eye macular ischemia in the context of vasculitis.ConclusionAt 3 years, intravitreal bevacizumab sustained significant visual improvement of 2.7 lines and significant foveal flattening of 98 μm in a wide variety of inflammatory ocular diseases without major complications after a median of 3 injections.     

Neonatal abstinence syndrome: management and current concepts

Neonatal abstinence syndrome (NAS), a constellation of predominantly autonomic, neurological and gastrointestinal symptoms, is caused by neonatal withdrawal from in utero exposure of maternal misuse of illicit or prescribed drugs. The severity of NAS depends on time, type and combination of drugs taken and the feto-maternal metabolic rate. The physical and psychological consequences of NAS are manifold, contributing to the difficulty in its diagnosis and management. Most babies exposed to opioids in utero require some form of treatment, either supportive or pharmacological treatment. Treatment is guided using standardised clinical scoring systems the most common being the Modified Finnegan Score. Although NAS is diagnosed clinically other possible diagnoses must be considered and toxicological confirmation is often helpful. The long-term neurodevelopmental side effects of NAS are yet to be fully explored. Early multidisciplinary intervention is required, and family integrated care should be actively encouraged. This paper summarises the symptomatology, investigations and current proposed management of NAS.     

Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues

Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S−) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S− was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S−). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.     

Pneumothorax preceding pulmonary blastoma in a child

Serial plain radiographic, ultrasound and CT findings of an unusual case of pulmonary blastoma are described with a review of the literature.     

The Kheda malaria project: the case for environmental control

The Kheda project experience has shown that bio-environmentalcontrol of malaria is feasible, cost effective and ecologicallysound. It clearly brings out the need to consider health issuesat the planning stage of all developments. Bio-environmentalcontrol of malaria is suggested as the first line of attackfor the control of mosquitoes, malaria and other mosquito-bornediseases. Insecticides may be reserved for short-term use. Thiswill enable judicious and selective use of insecticides in solelyepidemic situations. The growing problem of resistance to insecticidesin mosquitoes as well as environmental pollution, can then besolved on a long term basis.