A Case of 22q11.2 Deletion Syndrome with Peters Anomaly,Congenital Glaucoma,and Heterozygous Mutation in CYP1B1

We read with interest the recent publication by Tarlan and colleagues1 Tarlan B, Kiratli H, Kilic E, et al. A case of 22q11.2 deletion syndrome with right microphthalmia and left corneal staphyloma. Ophthalmic Genet 2013; [Epub ahead of print][PubMed], [Web of Science ®] , [Google Scholar] describing a patient with 22q11.2 deletion syndrome and ocular features of right microphthalmia and left anterior segment dysgenesis. While anterior segment dysgenesis disorders are occasionally reported with 22q11.2 deletions,2–5 Casteels I, Devriendt K. Unilateral Peters’ anomaly in a patient with DiGeorge syndrome. J Pediatr Ophthalmol Strabismus 2005;42:311–313 Binenbaum G, McDonald-McGinn DM, Zackai EH, et al. Sclerocornea associated with the chromosome 22q11.2 deletion syndrome. Am J Med Genet A 2008;146:904–909 Casteels I, Casaer P, Gewillig M, et al. Ocular findings in children with a microdeletion in chromosome 22q11.2. Eur J Pediatr 2008;167:751–755 Erdogan MK, Utine GE, Alanay Y, Aktas D. Unilateral Peters’ anomaly in an infant with 22q11.2 deletion syndrome. Clin Dysmorphol 2008;17:289–290  this remains a rare association. We report here an 8-year-old patient with 22q11.2 deletion syndrome and bilateral Peters anomaly with congenital glaucoma; in addition, our patient was found to have a single heterozygous mutation in CYP1B1, c.83C?>?T, p.(Ser28Trp).     

Sterilization of Drug-Loaded Composite Coatings for Implantable Glucose Biosensors

Background:An anti-inflammatory drug-loaded composite coating (dexamethasone-loaded poly (lactic-co-glycolic acid) [PLGA] microspheres/polyvinyl alcohol [PVA] hydrogel) was previously developed to counter the foreign body reaction to a fully implantable continuous glucose monitoring biosensor. The long-term sensor functionality was ensured in the presence of the drug-loaded composite coating thus facilitating better diabetes control and management. In order to advance such a drug-device combination product toward clinical testing, addressing sterilization remains a key step due to the heterogeneity of the product components. The main objective of this research was to investigate the effect of two terminal sterilization techniques: gamma radiation and ethylene oxide (EO) on the stability of the anti-inflammatory coatings as well as retention of the glucose sensing ability of the implantable sensor.Method:The composite coatings, their individual components, and the glucose-sensing elements of the biosensor were subjected to low-temperature gamma radiation and EO cycles. Detailed characterization was conducted on all components before and after sterilization.Results:Exposure to gamma radiation affected dexamethasone crystallinity and glucose response linearity of the sensing element, whereas physical aging of microspheres in composite coatings was observed poststerilization with EO. Despite these effects, dexamethasone drug release from coatings was not significantly affected by either technique.Conclusion:The research findings indicate that both sterilization techniques are feasible for the sterilization of the dexamethasone-loaded PLGA microspheres/PVA hydrogel composite coatings, while EO was preferred for the sterilization of the glucose-sensing element of the biosensor.     

Processing gender: lived experiences of reproducing and transforming gender norms over the life course of young people in Northern Uganda

The years between 10–19 represent a critical stage of human development during which boys and girls learn and embody socially constructed gender norms, with long-term implications for their sexual and reproductive health. This ethnographic cohort study sought to understand how gendered norms and practices develop during the transition from child to young adult in post-conflict northern Uganda. A total of 60 girls and boys aged 10–19 were selected using purposive sampling for in-depth interviews over a three-year period; 47 individuals completed all four interviews. Drawing on feminist theory and an ecological perspective, findings were used to create a conceptual framework displaying the experiences of young people navigating patriarchal and alternative norms, emphasising their lived processes of performing and negotiating norms within six key domains (work, puberty, family planning, intimate partner relations, child discipline and alcohol). The framework identifies: (1) personal factors (knowledge, agency and aspirations); (2) social factors (socialisation processes, capital, costs and consequences); and (3) structural factors (health/educational systems, religious institutions, government policies) which may encourage young people towards one norm or another as they age. These findings can inform policies and programmes to transform gender norms and promote equitable, healthy relationships.     

Long-Term Correction of Sandhoff Disease Following Intravenous Delivery of rAAV9 to Mouse Neonates

G_M2 gangliosidoses are severe neurodegenerative disorders resulting from a deficiency in β-hexosaminidase A activity and lacking effective therapies. Using a Sandhoff disease (SD) mouse model (Hexb^−/−) of the G_M2 gangliosidoses, we tested the potential of systemically delivered adeno-associated virus 9 (AAV9) expressing Hexb cDNA to correct the neurological phenotype. Neonatal or adult SD and normal mice were intravenously injected with AAV9-HexB or –LacZ and monitored for serum β-hexosaminidase activity, motor function, and survival. Brain G_M2 ganglioside, β-hexosaminidase activity, and inflammation were assessed at experimental week 43, or an earlier humane end point. SD mice injected with AAV9-LacZ died by 17 weeks of age, whereas all neonatal AAV9-HexB–treated SD mice survived until 43 weeks (P < 0.0001) with only three exhibiting neurological dysfunction. SD mice treated as adults with AAV9-HexB died between 17 and 35 weeks. Neonatal SD-HexB–treated mice had a significant increase in brain β-hexosaminidase activity, and a reduction in G_M2 ganglioside storage and neuroinflammation compared to adult SD-HexB– and SD-LacZ–treated groups. However, at 43 weeks, 8 of 10 neonatal-HexB injected control and SD mice exhibited liver or lung tumors. This study demonstrates the potential for long-term correction of SD and other G_M2 gangliosidoses through early rAAV9 based systemic gene therapy.     

Phase 1 Randomized,Double-Blind,Placebo-Controlled Study of RG7667, an Anticytomegalovirus Combination Monoclonal Antibody Therapy,in Healthy Adults

Cytomegalovirus can cause debilitating and life-threatening disease in newborns infected in utero and immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n = 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n = 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n = 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT01496755","term_id":"NCT01496755"}}NCT01496755.)     

High‐resolution MALDI‐FT‐ICR MS imaging for the analysis of metabolites from formalin‐fixed,paraffin‐embedded clinical tissue samples

We present the first analytical approach to demonstrate the in situ imaging of metabolites from formalin‐fixed, paraffin‐embedded (FFPE) human tissue samples. Using high‐resolution matrix‐assisted laser desorption/ionization Fourier‐transform ion cyclotron resonance mass spectrometry imaging (MALDI‐FT‐ICR MSI), we conducted a proof‐of‐principle experiment comparing metabolite measurements from FFPE and fresh frozen tissue sections, and found an overlap of 72% amongst 1700 m/z species. In particular, we observed conservation of biomedically relevant information at the metabolite level in FFPE tissues. In biomedical applications, we analysed tissues from 350 different cancer patients and were able to discriminate between normal and tumour tissues, and different tumours from the same organ, and found an independent prognostic factor for patient survival. This study demonstrates the ability to measure metabolites in FFPE tissues using MALDI‐FT‐ICR MSI, which can then be assigned to histology and clinical parameters. Our approach is a major technical, histochemical, and clinicopathological advance that highlights the potential for investigating diseases in archived FFPE tissues. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Systemic disease in Peromyscus leucopus associated with Borrelia burgdorferi infection

Sixteen wild Peromyscus leucopus, trapped for the establishment of a breeding colony, developed signs of neurological damage (trembling, incoordination, circling, head tilt, and lameness of the rear legs) 2-47 days after capture in southern Wisconsin. Spirochetes were cultured from the brain of 5/11 mice, and Borrelia burgdorferi was cultured from 1 brain. A spirochete was isolated from the bladder of 1 mouse. The spirochete was identified by fluorescent antibody staining with the monoclonal antibody specific for B. burgdorferi, H5332. Serum antibodies to the spirochete were found in 14/15 mice. Negative results were obtained in all tests for viruses and bacteria, including Listeria (2/2), Mycoplasma (2/2), mouse hepatitis virus (10/10), Theilers's encephalomyelitis virus (GD VII) (8/8), REO 3 virus (2/2), and lymphocytic choriomeningitis virus (4/4). There was no bacterial growth from brains cultured on eosin methylene blue or blood agar (3/3). Histologic lesions included nonsuppurative cellular infiltrates in the brain, kidney, liver, and lung. Three outbred Swiss-Webster mice were inoculated orally with a suspension of the brain in BSKII medium, and 3 were inoculated with unpassed B. burgdorferi cultured from the brain of a P. leucopus with motor dysfunction. Five of the inoculated mice developed antibody titers of 1:128; one mouse was positive at 1:256. Motor signs of neurologic damage developed in 3/6 mice 2-24 weeks post-inoculation, and B. burgdorferi was detected in the brains of 2 mice by isolation and by fluorescent antibody.     

Single amino acid mutation of FCγ receptor is associated with the development of heparin-induced thrombocytopenia

Summary. Heparin-induced thrombocytopenia (HIT) is mediated by a heparin-dependent antibody/platelet factor 4/heparin complex binding to platelets via the FCγ receptor (type IIA). A single base polymorphism at position 131 of FeγRIIA changes the native arginine to histidine. In the presence of murine monoclonal IgG₁ the former phenotype (FcγRIIA^Arg131) is functionally characterized by strong platelet aggregation (high responder) and the latter (Fc7RIIA^Hls131) by poor aggregation (low responder). In the presence of human IgGa the opposite response is observed. It has recently been shown that the heparin-dependent antibody is predominantly of this subclass. We hypothesize that a relationship exists between FcγRIIA^Hls131 and the development of HIT. We studied 24 normal individuals and 20 HIT patients using VM58, a murine monoclonal IgG₁, to characterize the phenotype by platelet aggregrometry, and PCR products, amplified with primers bordering the FC7RIIA polymorphism and hybridized with oligonucleotide probes specific for the single base mutation, to determine the genotype. The distribution of phenotypes and genotypes in the two populations differed, with a greater prevalence of the FcγRIIA^His131 allele in the HIT patient population. Homozygous Fc7RIIA^Arg131 individuals were absent from this group. We conclude that the presence of the Fc7RIIA^His131 allele is associated with a predisposition to HIT.