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1.
J Anim Ecol ; 90(12): 2875-2887, 2021 12.
Article in English | MEDLINE | ID: mdl-34492121

ABSTRACT

Individual specialisations in behaviour are predicted to arise where divergence benefits fitness. Such specialisations are more likely in heterogeneous environments where there is both greater ecological opportunity and competition-driven frequency dependent selection. Such an effect could explain observed differences in rates of individual specialisation in habitat selection, as it offers individuals an opportunity to select for habitat types that maximise resource gain while minimising competition; however, this mechanism has not been tested before. Here, we use habitat selection functions to quantify individual specialisations while foraging by black-legged kittiwakes Rissa tridactyla, a marine top predator, at 15 colonies around the United Kingdom and Ireland, along a gradient of environmental heterogeneity. We find support for the hypothesis that individual specialisations in habitat selection while foraging are more prevalent in heterogeneous environments. This trend was significant across multiple dynamic habitat variables that change over short time-scales and did not arise through site fidelity, which highlights the importance of environmental processes in facilitating behavioural adaptation by predators. Individual differences may drive evolutionary processes, and therefore these results suggest that there is broad scope for the degree of environmental heterogeneity to determine current and future population, species and community dynamics.


Subject(s)
Charadriiformes , Ecosystem , Animals , United Kingdom
2.
Mar Pollut Bull ; 170: 112636, 2021 Sep.
Article in English | MEDLINE | ID: mdl-34153853

ABSTRACT

Seabird eggs are considered a favourable matrix for monitoring marine pollutants and are widely used as higher trophic level indicators. Concentrations of Polycyclic aromatic hydrocarbons (Σ15PAH) were determined in the eggs of four piscivorous seabirds in Ireland from multiple colonies for the first time, Common Guillemot Uria aalge, Northern Gannet Morus bassanus, Common Tern Sterna hirundo and Arctic Tern S. paradisaea. PAH concentrations were generally lower than levels detected in eggs from other seabird studies and considerably lower than concentrations associated with no adverse effect in the eggs of domestic avian species. This study indicates potential site and species differences in PAH concentrations. Baseline data of PAHs in a range of seabird species from this study may provide an important reference point should a major pollution event occur in European waters, such as an oil spill.


Subject(s)
Charadriiformes , Polycyclic Aromatic Hydrocarbons , Animals , Birds , Environmental Monitoring , Ireland
3.
Chemosphere ; 283: 131161, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34144293

ABSTRACT

Guillemot eggs from multiple Irish colonies and one Welsh colony were analysed for legacy pollutants such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and other organochlorine compounds (OCs), as well as metals. Stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) were measured in eggs to understand the influence of diet on contaminant levels detected. Wide-scope target and suspect screening techniques were used on a single guillemot egg, providing novel information on contaminants of emerging concern. Stable isotope ratio analysis showed that guillemots from Great Saltee Island and Lambay Island (Ireland's east coast) had a similar carbon source (δ13C) and fed at similar trophic levels (δ15N), pollutant levels were higher in eggs from Lambay Island near Dublin, Ireland's industrialised capital city. Guillemot eggs from Aughris Head (Atlantic west coast of Ireland), and Skomer Island (Wales) had differing isotopic niches to other colonies. Egg samples from Aughris Head had the lowest levels of pollutants in this study (with the exception of mercury) and amongst the lowest levels reported worldwide. In contrast, Skomer Island had the highest level of pollutants with higher concentrations of Σ16PCB, Σ6PBDE and HCB than Irish colonies, most likely a result of its proximity to historically industrial areas. Levels of PCBs, p,p' -DDE and mercury in guillemot eggs have decreased over time according to this study, in concurrence with worldwide trends. Levels of pollutants in guillemot eggs, in this study, fall below existing thresholds for adverse effects in other species, with the exception of mercury.


Subject(s)
Charadriiformes , Environmental Pollutants , Polychlorinated Biphenyls , Animals , Eggs/analysis , Environmental Monitoring , Environmental Pollutants/analysis , Ireland , Polychlorinated Biphenyls/analysis , Wales
4.
Mar Pollut Bull ; 168: 112400, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33957494

ABSTRACT

Higher levels of persistent pollutants (Σ16PCB, Σ6PBDE, ΣHCH, ΣDDT, ΣCHL) were detected in fresh eggs of Common Terns Sterna hirundo from Rockabill Island near Dublin (Ireland's industrialised capital city) compared to Common and Arctic Terns S. paradisaea from Ireland's west coast. Intra-clutch variation of pollutant levels in Common Terns was shown to be low, providing further evidence that random sampling of one egg may be an appropriate sampling strategy. Significant differences in pollutant concentrations were detected between fresh and abandoned eggs on Rockabill. However, abandoned eggs can still provide a useful approximation of pollutants in bird eggs if non-destructive sampling is preferred. Levels of p,p' -DDE in tern eggs have decreased over time according to this study, in concurrence with worldwide trends. Results in this study fall below toxicological thresholds for birds and OSPARs EcoQO thresholds set for Common Tern eggs, except for mercury and HCH in the west coast.


Subject(s)
Charadriiformes , Environmental Pollutants , Mercury , Animals , Environmental Pollutants/analysis , Ireland , Islands , Mercury/analysis
5.
Environ Pollut ; 268(Pt A): 115723, 2021 Jan 01.
Article in English | MEDLINE | ID: mdl-33070066

ABSTRACT

Seabird eggs are considered a favourable matrix for monitoring marine pollutants and are widely used as higher trophic level indicators. Persistent organic pollutants such as polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs) and other organochlorine compounds (OCs) as well as metals have been shown to have deleterious impacts on seabirds. The Northern Gannet Morus bassanus is an avian sentinel; the largest breeding seabird in Ireland and an obligate piscivore. Gannet eggs were collected from two island colonies off the east coast of Ireland in locations with divergent history of industrialisation. Contaminant levels were measured and differences in concentrations between colonies compared. Stable isotope ratios of carbon (δ13C) and nitrogen (δ15N) were measured in each egg to understand the influence of diet and trophic position on contaminant levels detected. Significantly higher levels of Σ14PCBs, Σ7PBDEs and total mercury were detected in Gannet eggs from Lambay Island near Dublin (Ireland's industrialised capital city) compared to Great Saltee Island. No differences were observed in levels of other OCs (HCB, ΣHCH, ΣCHL, ΣDDT) between the two colonies. Though Gannets travel significant distances when foraging for food, tracking studies have demonstrated that birds from proximal breeding colonies maintain exclusive feeding areas. Stable isotope ratio analysis in this study demonstrated that Gannets at both locations occupy similar dietary niches, indicating that dietary differences may not be the driver of differing contaminant levels between colonies. Levels of persistent pollutants in the Gannet eggs fall below most existing thresholds for adverse effects and are within internationally reported values. Recent population growth and range expansion of Gannets in Ireland suggest that persistent pollutants are not having an immediate impact on the Gannet population. This study will inform potential monitoring programmes that can help Ireland achieve good environmental status under the European Union's Marine Strategy Framework Directive.


Subject(s)
Environmental Pollutants , Morus , Polychlorinated Biphenyls , Animals , Birds , Environmental Monitoring , Environmental Pollutants/analysis , Ireland , Islands , Polychlorinated Biphenyls/analysis
6.
Otol Neurotol ; 41(7): 978-985, 2020 08.
Article in English | MEDLINE | ID: mdl-32658404

ABSTRACT

OBJECTIVES: To investigate novel variants in hearing loss genes and clinical factors affecting audiometric outcomes of cochlear implant (CI) patients. BACKGROUND: Approximately 50% of hearing loss has a genetic etiology, with certain genetic variants more prevalent in specific ethnic groups. Different variants and some clinical variables including inner ear malformations result in different prognoses or clinical outcomes after CI. METHODS: Medical and genetic testing records of pediatric CI patients were reviewed for clinical variables. Minor allele frequencies of variants were obtained from Genome Aggregation Database (gnomAD) and variants were classified for pathogenicity. Standard statistical testing was done using Fisher's exact, Wilcoxon, and Spearman correlation tests. RESULTS: Eighteen CI patients with genetic test results had pathogenic variants, including six patients with syndromic hearing loss and six patients with known GJB2 variants. Novel pathogenic variants were noted in CHD7, ADGRV1, and ARID1B, with variants in the latter two genes identified in Hispanic patients. Overall, carriage of genetic variants was associated with better pre-CI audiometric thresholds at 2000 Hz (p = 0.048). On the other hand, post-CI thresholds were significantly worse in patients with inner ear malformations, particularly in patients with atretic cochlear nerve canals. CONCLUSION: Four novel pathogenic variants were identified, which contributes to knowledge of allelic spectrum for hearing loss especially in Hispanic patients. In this cohort, carriage of pathogenic variants particularly of GJB2 variants was associated with better pre-CI audiometric thresholds, while patients with inner ear malformations had worse post-CI audiometric thresholds.


Subject(s)
Cochlear Implantation , Cochlear Implants , Deafness , Hearing Loss , Child , Ethnicity/genetics , Hearing Loss/surgery , Humans
7.
Proc Biol Sci ; 286(1904): 20190795, 2019 06 12.
Article in English | MEDLINE | ID: mdl-31161906

ABSTRACT

Environmental heterogeneity shapes the uneven distribution of resources available to foragers, and is ubiquitous in nature. Optimal foraging theory predicts that an animal's ability to exploit resource patches is key to foraging success. However, the potential fitness costs and benefits of foraging in a heterogeneous environment are difficult to measure empirically. Heterogeneity may provide higher-quality foraging opportunities, or alternatively could increase the cost of resource acquisition because of reduced patch density or increased competition. Here, we study the influence of physical environmental heterogeneity on behaviour and reproductive success of black-legged kittiwakes, Rissa tridactyla. From GPS tracking data at 15 colonies throughout their British and Irish range, we found that environments that were physically more heterogeneous were associated with longer trip duration, more time spent foraging while away from the colony, increased overlap of foraging areas between individuals and lower breeding success. These results suggest that there is greater competition between individuals for finite resources in more heterogeneous environments, which comes at a cost to reproduction. Resource hotspots are often considered beneficial, as individuals can learn to exploit them if sufficiently predictable. However, we demonstrate here that such fitness gains can be countered by greater competition in more heterogeneous environments.


Subject(s)
Behavior, Animal , Charadriiformes/physiology , Ecosystem , Animals , Breeding , Feeding Behavior , Ireland , Reproduction , Time Factors , United Kingdom
8.
J Anim Ecol ; 88(1): 138-153, 2019 01.
Article in English | MEDLINE | ID: mdl-30353538

ABSTRACT

Habitat management to restore or create breeding sites may allow metapopulations to increase in size and reduce the risk of demographic stochasticity or disasters causing metapopulation extinction. However, if newly restored or created sites are of low quality, they may act as sinks that draw individuals away from better quality sites to the detriment of metapopulation size. Following intensive conservation effort, the metapopulation of roseate tern (Sterna dougallii) in NW Europe is recovering from a large crash in numbers, but most former colonies remain unoccupied and hence are potential targets for restoration. To inform conservation efforts, we studied the dynamics of this metapopulation with a multistate integrated population model to assess each of the three main colonies for important demographic contributors to population growth rate, source/sink status and possible density dependence. All three study colonies are managed for roseate terns (and other tern species) in similar ways, but the demographic processes vary considerably between colonies. The largest colony is a source involved in almost all dispersal, and its growth is determined by survival rates and productivity. Productivity and juvenile apparent survival at the largest colony appear to be density-dependent. Although the mechanisms are unclear, this may provide an increasing impetus for emigration of recruits to other colonies in future. The smallest of the three colonies is a sink, relying on immigration for its growth. Simulation models suggest the metapopulation would be c. 10% larger in the absence of dispersal to the sink colony. This work indicates that, due to variable site quality, aims to enhance both distribution and size of metapopulations may be mutually exclusive. In this case, before future attempts to encourage recolonisation of former sites, assessments of site suitability should be undertaken, focusing on food availability and isolation from predators to maximise the likelihood of attaining levels of productivity and survival that avoid creation of a sink population to the detriment of the overall metapopulation size.


Subject(s)
Charadriiformes , Animals , Demography , Ecosystem , Europe , Population Dynamics
9.
Int Arch Otorhinolaryngol ; 22(3): 317-329, 2018 Jul.
Article in English | MEDLINE | ID: mdl-29983775

ABSTRACT

Introduction A majority of otolaryngologists have not had direct experience with many vaccine-preventable diseases since the creation of national vaccination programs. Despite the elimination of endemic transmission of some of these diseases in the United States, outbreaks can occur anywhere and still pose a threat to public health around the world. Recent outbreaks and changing trends in exemption rates indicate that it is important for physicians to maintain a working knowledge of how these diseases present and of the recommended treatment guidelines. Objectives This review will evaluate the current state of vaccination rates, vaccine exemption rates and disease incidence in the United States and in the world. It will also examine the clinical presentation and treatment recommendations of these diseases. Data Synthesis United States estimated vaccination rates, vaccine exemption rates and vaccine-preventable disease incidences were obtained from data compiled by the Centers for Disease Control and Prevention. World vaccination rates and disease incidences were obtained from the World Health Organization databases, which compile official figures reported by member states. A PubMed literature review provided information on the current state of vaccination exemptions and outbreaks in the United States. Conclusion Vaccination and vaccine exemption rates continue to put the United States and many areas of the world at risk for outbreaks of vaccine-preventable diseases. Clinical guidelines should be reviewed in the event of a local outbreak.

10.
Int. arch. otorhinolaryngol. (Impr.) ; 22(3): 317-329, July-Sept. 2018. tab, graf
Article in English | LILACS | ID: biblio-975585

ABSTRACT

Abstract Introduction A majority of otolaryngologists have not had direct experience with many vaccine-preventable diseases since the creation of national vaccination programs. Despite the elimination of endemic transmission of some of these diseases in the United States, outbreaks can occur anywhere and still pose a threat to public health around the world. Recent outbreaks and changing trends in exemption rates indicate that it is important for physicians to maintain a working knowledge of how these diseases present and of the recommended treatment guidelines. Objectives This review will evaluate the current state of vaccination rates, vaccine exemption rates and disease incidence in the United States and in the world. It will also examine the clinical presentation and treatment recommendations of these diseases. Data Synthesis United States estimated vaccination rates, vaccine exemption rates and vaccine-preventable disease incidences were obtained from data compiled by the Centers for Disease Control and Prevention. World vaccination rates and disease incidences were obtained from the World Health Organization databases, which compile official figures reported by member states. A PubMed literature review provided information on the current state of vaccination exemptions and outbreaks in the United States. Conclusion Vaccination and vaccine exemption rates continue to put the United States and many areas of the world at risk for outbreaks of vaccine-preventable diseases. Clinical guidelines should be reviewed in the event of a local outbreak.


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Disease Outbreaks/statistics & numerical data , Vaccination/statistics & numerical data , Otolaryngologists/education , Asia , Rubella/prevention & control , Rubella/epidemiology , United States , Americas , Vaccines , Global Health/statistics & numerical data , Incidence , Africa , Diphtheria/prevention & control , Diphtheria/epidemiology , Europe , Disease Eradication/statistics & numerical data , Haemophilus Infections/prevention & control , Measles/prevention & control , Measles/epidemiology , Mumps/prevention & control , Mumps/epidemiology
11.
Laryngoscope ; 128(11): 2619-2624, 2018 11.
Article in English | MEDLINE | ID: mdl-29729014

ABSTRACT

OBJECTIVES/HYPOTHESIS: To determine the incidence of cochlear implant failure and to examine surgical and audiological outcomes. STUDY DESIGN: Retrospective review, case series. METHODS: This study sought indications for revision surgery, surgical findings, and outcomes, and audiological outcomes in pediatric cochlear implant patients. Pre- and postcochlear reimplantation word recognition performance was analyzed using a modified version of the Pediatric Ranked Order Speech Perception (PROSPER) score. RESULTS: Over a 20-year period, a total of 868 cochlear implants were performed in 578 patients. The overall institutional reimplant rate was 5.9%. The indications for explantation were hard failure (30), soft failure (23), and medical/surgical indication (13). A significant portion of devices belonged to vendor recalled batches (15) or were damaged by head trauma (eight). Full electrode insertion was achieved in all 62 reimplantations. Post-reimplantation Boston Children's Hospital modified PROSER scores were either stable or improved compared to pre-reimplantation scores. CONCLUSIONS: The need for cochlear implant revision/reimplantation is infrequent, but the rate is not inconsequential. Hard and soft device failures account for the majority of reimplants. Surgical complications during reimplantation is low, and post-reimplantation audiological performance is excellent. LEVEL OF EVIDENCE: 4. Laryngoscope, 2619-2624, 2018.


Subject(s)
Cochlear Implantation/statistics & numerical data , Cochlear Implants , Deafness/surgery , Prosthesis Failure , Reoperation , Child, Preschool , Cochlear Implantation/methods , Deafness/psychology , Female , Humans , Infant , Male , Postoperative Period , Reoperation/methods , Reoperation/statistics & numerical data , Retrospective Studies , Speech Perception , Treatment Outcome
12.
Ecol Appl ; 27(7): 2074-2091, 2017 10.
Article in English | MEDLINE | ID: mdl-28653410

ABSTRACT

Population-level estimates of species' distributions can reveal fundamental ecological processes and facilitate conservation. However, these may be difficult to obtain for mobile species, especially colonial central-place foragers (CCPFs; e.g., bats, corvids, social insects), because it is often impractical to determine the provenance of individuals observed beyond breeding sites. Moreover, some CCPFs, especially in the marine realm (e.g., pinnipeds, turtles, and seabirds) are difficult to observe because they range tens to ten thousands of kilometers from their colonies. It is hypothesized that the distribution of CCPFs depends largely on habitat availability and intraspecific competition. Modeling these effects may therefore allow distributions to be estimated from samples of individual spatial usage. Such data can be obtained for an increasing number of species using tracking technology. However, techniques for estimating population-level distributions using the telemetry data are poorly developed. This is of concern because many marine CCPFs, such as seabirds, are threatened by anthropogenic activities. Here, we aim to estimate the distribution at sea of four seabird species, foraging from approximately 5,500 breeding sites in Britain and Ireland. To do so, we GPS-tracked a sample of 230 European Shags Phalacrocorax aristotelis, 464 Black-legged Kittiwakes Rissa tridactyla, 178 Common Murres Uria aalge, and 281 Razorbills Alca torda from 13, 20, 12, and 14 colonies, respectively. Using Poisson point process habitat use models, we show that distribution at sea is dependent on (1) density-dependent competition among sympatric conspecifics (all species) and parapatric conspecifics (Kittiwakes and Murres); (2) habitat accessibility and coastal geometry, such that birds travel further from colonies with limited access to the sea; and (3) regional habitat availability. Using these models, we predict space use by birds from unobserved colonies and thereby map the distribution at sea of each species at both the colony and regional level. Space use by all four species' British breeding populations is concentrated in the coastal waters of Scotland, highlighting the need for robust conservation measures in this area. The techniques we present are applicable to any CCPF.


Subject(s)
Animal Distribution , Birds/physiology , Feeding Behavior , Nesting Behavior , Animals , Charadriiformes/physiology , Ireland , Models, Biological , Population Density , United Kingdom
13.
Mar Pollut Bull ; 119(2): 171-174, 2017 Jun 30.
Article in English | MEDLINE | ID: mdl-28431743

ABSTRACT

Seabirds can interact with marine litter, mainly by entanglement or ingestion. The ingestion of plastics can lead to starvation or physical damage to the digestive tract. For chicks, it could additionally lead to reduced growth, affecting survival and fledging. This study quantified the ingestion of plastics by seabird chicks via an opportunistic sampling strategy. When ringing is carried out at colonies, birds may spontaneously regurgitate their stomach contents due to the stress or as a defence mechanism. Regurgitates were collected from nestlings of three different species: Black-legged Kittiwake (Rissa tridactyla, n=38), Northern Fulmar (Fulmarus glacialis, n=14) and Great Cormorant (Phalacrocorax carbo, n=28). Plastic was present in all species, with the highest frequency of occurrence (FO) in Northern Fulmar chicks (28.6%), followed by Black-legged Kittiwakes (7.9%) and Great Cormorants (7.1%). The observed load of plastics on chicks, which have not yet left the nest, highlights the pervasive nature of plastic pollution.


Subject(s)
Birds , Diet , Environmental Monitoring , Environmental Pollutants/toxicity , Plastics/toxicity , Animals , Charadriiformes , Feeding Behavior
14.
Mar Pollut Bull ; 117(1-2): 512-514, 2017 Apr 15.
Article in English | MEDLINE | ID: mdl-28189370

ABSTRACT

Plastic pollution has been the subject of much research in the last decade. Seabirds can mistake plastic fragments for prey, which can perforate or block the digestive tract and cause ulcers. Most commonly, seabirds accumulate this indigestible matter in their stomachs, obtaining no nutrition and may die from starvation. Certain species of seabirds however, have the ability of regurgitating indigestible matter in the form of pellets. This study aimed to investigate the ingestion of plastics by live seabirds through the examination of regurgitated pellets (n=92) from a Great Cormorant (Phalacrocorax carbo) breeding colony and a winter roost in Ireland. Plastic prevalence was consistently 3.2% at both sites. The presence of plastic litter highlights the fact that all species of seabird are susceptible to interact with marine litter regardless of feeding habits, although at different rates. More research is needed to understand the driving factors involved in plastic ingestion among different species.


Subject(s)
Birds , Environmental Monitoring , Gastrointestinal Contents , Plastics , Animals , Ireland , Waste Products , Water Pollutants
15.
J Clin Sleep Med ; 9(7): 681-6, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23853562

ABSTRACT

STUDY OBJECTIVES: The aim was to determine the feasibility of using an unattended 2-channel device to screen for obstructive sleep apnea in a population of high-risk patients using a targeted, case-finding strategy. The case finding was based on the presence of risk factors not symptoms in the studied population. METHODS: The study took place from June 2007 to May 2008 in rural and metropolitan Queensland and New South Wales. Family doctors were asked to identify patients with any of the following: BMI > 30, type 2 diabetes, treated hypertension, ischemic heart disease. Participants applied the ApneaLink+O2 at home for a single night. The device recorded nasal flow and pulse oximetry. Data were analyzed by proprietary software, then checked and reported by either of two sleep physicians. RESULTS: 1,157 patients were recruited; mean age 53 ± 14.6, M/F% = 62/38, mean BMI = 31.8, obesity = 35%, diabetes = 16%, hypertension = 39%, IHD = 5%, Mean Epworth Sleepiness Scale score (ESS) = 8.3. The prevalence of unrecognized OSA was very high: 71% had an AHI > 5/h, 33% had an AHI > 15/h, and 16% had an AHI > 30/h. The ApneaLink+O2 device yielded technically adequate studies in 93% of cases. CONCLUSION: The study shows that a "real world" simple low cost case finding and management program, based on unattended home monitoring for OSA, can work well in a population with risk factors and comorbidities associated with OSA, independent of the presence of symptoms. The prevalence of unrecognized OSA was very high.


Subject(s)
Polysomnography/instrumentation , Polysomnography/methods , Primary Health Care/methods , Sleep Apnea, Obstructive/diagnosis , Body Mass Index , Diabetes Mellitus, Type 2/complications , Feasibility Studies , Female , Humans , Hypertension/complications , Male , Middle Aged , Myocardial Ischemia/complications , New South Wales , Obesity/complications , Queensland , Sleep Apnea, Obstructive/complications
16.
Int J Pharm Compd ; 17(5): 370-4, 2013.
Article in English | MEDLINE | ID: mdl-24459781

ABSTRACT

Chemical penetration enhancers are utilized in topical preparations as a method for enhancing permeation of drugs across the skin. In particular, they are utilized for transdermal delivery of medications in an attempt to produce a systemic response, to avoid first-pass metabolism, and to decrease the gastrointestinal transit time observed with oral medications. A review of the selection of chemical penetration enhancers, their mechanism of action, the most common chemical penetration enhancers in each class, and alternatives will be discussed in detail.


Subject(s)
Excipients/chemistry , Pharmaceutical Preparations/administration & dosage , Skin Absorption , Administration, Cutaneous , Drug Delivery Systems , Humans , Pharmaceutical Preparations/metabolism
17.
Hear Res ; 277(1-2): 28-36, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21530627

ABSTRACT

Gene-based therapeutics are being developed as novel treatments for genetic hearing loss. One roadblock to effective gene therapy is the identification of vectors which will safely deliver therapeutics to targeted cells. The cellular heterogeneity that exists within the cochlea makes viral tropism a vital consideration for effective inner ear gene therapy. There are compelling reasons to identify a viral vector with tropism for organ of Corti supporting cells. Supporting cells are the primary expression site of connexin 26 gap junction proteins that are mutated in the most common form of congenital genetic deafness (DFNB1). Supporting cells are also primary targets for inducing hair cell regeneration. Since many genetic forms of deafness are congenital it is necessary to administer gene transfer-based therapeutics prior to the onset of significant hearing loss. We have used transuterine microinjection of the fetal murine otocyst to investigate viral tropism in the developing inner ear. For the first time we have characterized viral tropism for supporting cells following in utero delivery to their progenitors. We report the inner ear tropism and potential ototoxicity of three previously untested vectors: early-generation adenovirus (Ad5.CMV.GFP), advanced-generation adenovirus (Adf.11D) and bovine adeno-associated virus (BAAV.CMV.GFP). Adenovirus showed robust tropism for organ of Corti supporting cells throughout the cochlea but induced increased ABR thresholds indicating ototoxicity. BAAV also showed tropism for organ of Corti supporting cells, with preferential transduction toward the cochlear apex. Additionally, BAAV readily transduced spiral ganglion neurons. Importantly, the BAAV-injected ears exhibited normal hearing at 5 weeks of age when compared to non-injected ears. Our results support the use of BAAV for safe and efficient targeting of supporting cell progenitors in the developing murine inner ear.


Subject(s)
Adenoviridae/genetics , Deafness/therapy , Dependovirus/genetics , Gene Transfer Techniques , Genetic Therapy/methods , Genetic Vectors , Labyrinth Supporting Cells/virology , Organ of Corti/virology , Viral Tropism , Acoustic Stimulation , Animals , Audiometry, Pure-Tone , Auditory Threshold , Deafness/genetics , Deafness/physiopathology , Evoked Potentials, Auditory, Brain Stem , Gene Transfer Techniques/adverse effects , Genetic Therapy/adverse effects , Genetic Vectors/adverse effects , Gestational Age , Green Fluorescent Proteins/biosynthesis , Green Fluorescent Proteins/genetics , Labyrinth Supporting Cells/metabolism , Mice , Mice, Inbred BALB C , Microinjections , Microscopy, Fluorescence , Organ of Corti/embryology , Organ of Corti/metabolism , Organ of Corti/physiopathology , Stem Cells/virology , Transduction, Genetic
18.
Am J Med Genet A ; 152A(3): 646-52, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20186779

ABSTRACT

Mutations in miRNA genes have been implicated in hearing loss in human families and mice. It is also possible that mutations in miRNA binding sites of inner ear targets alter gene expression levels and lead to hearing loss. To investigate these possibilities we screened predicted target genes of the miR-183 miRNA cluster known to be expressed in the inner ear sensory epithelium. In one Iranian family segregating autosomal recessive non-syndromic hearing loss (ARNSHL), we identified a homozygous variant in a predicted miR-96/182 binding site in the 3'UTR of the RDX (DFNB24) gene. However, in vitro functional studies showed that this site is not a functional target for miR-96/182. We extended our study to include the miR-183 genes themselves and 24 additional predicted target genes of the miRNA-183 cluster. Screening these miRNAs and target sequences in numerous families segregating either autosomal dominant non-syndromic deafness (ADNSHL) or ARNSHL did not identify any potential deafness-causing mutations. These results suggest that mutations disrupting gene regulation by the miR-183 cluster are not a common cause of human hearing loss.


Subject(s)
Deafness/genetics , MicroRNAs/genetics , Mutation , 3' Untranslated Regions , Animals , Base Sequence , Binding Sites/genetics , Cytoskeletal Proteins/genetics , DNA Primers/genetics , Female , Genes, Dominant , Genes, Recessive , Homozygote , Humans , Male , Membrane Proteins/genetics , Mice , Multigene Family , Pedigree , Sequence Homology, Nucleic Acid
19.
Int J Pharm Compd ; 14(4): 301-4, 2010.
Article in English | MEDLINE | ID: mdl-23965536

ABSTRACT

Percutaneous absorption is affected by numerous factors. Whether they are internal or external factors, the compounding pharmacist must collectively consider these variables in order to provide a safe and effective topical preparation for the patient. By considering the physiochemical and dermal factors that affect percutaneous absorption of a medication, an effective topical medication can be formulated to treat the patient's specific indication. Furthermore, this article will review the background information necessary to formulate transdermal prescriptions for their patients.

20.
Mol Ther ; 16(2): 224-36, 2008 Feb.
Article in English | MEDLINE | ID: mdl-18223547

ABSTRACT

Development of effective therapeutics for hearing loss has proven to be a slow and difficult process, evidenced by the lack of restorative medicines and technologies currently available to the otolaryngologist. In large part this is attributable to the limited regenerative potential in cochlear cells and the secondary degeneration of the cochlear architecture that commonly follows sensorineural hearing impairment. Therapeutic advances have been made using animal models, particularly in regeneration and remodeling of spiral ganglion neurons, which retract and die following hair cell loss. Natural regeneration in avian and reptilian systems provides hope that replacement of hair cells is achievable in humans. The most exciting recent advancements in this field have been made in the relatively new areas of cellular replacement and gene therapy. In this review we discuss recent developments in gene- and cell-based therapy for hearing loss, including detailed analysis of therapeutic mechanisms such as RNA interference and stem cell transplantation, as well as in utero delivery to the mammalian inner ear. We explore the advantages and limitations associated with the use of these strategies for inner ear restoration.


Subject(s)
Disease Models, Animal , Hearing Loss/therapy , Animals , Genetic Therapy/methods , Hearing Loss/genetics , Hearing Loss/pathology , Humans , Models, Theoretical , RNA Interference , Stem Cell Transplantation/methods
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