Reproducible Synthesis of Biocompatible Albumin Nanoparticles Designed for Intra-articular Administration of Celecoxib to Treat Osteoarthritis.

Osteoarthritis (OA) is the most common form of arthritis, with intra-articular (IA) delivery of therapeutics being the current best option to treat pain and inflammation. However, IA delivery is challenging due to the rapid clearance of therapeutics from the joint and the need for repeated injections. Thus, there is a need for long-acting delivery systems that increase the drug retention time in joints with the capacity to penetrate OA cartilage. As pharmaceutical utility also demands that this is achieved using biocompatible materials that provide colloidal stability, our aim was to develop a nanoparticle (NP) delivery system loaded with the COX-2 inhibitor celecoxib that can meet these criteria. We devised a reproducible and economical method to synthesize the colloidally stable albumin NPs loaded with celecoxib without the use of any of the following conditions: high temperatures at which albumin denaturation occurs, polymer coatings, oils, Class 1/2 solvents, and chemical protein cross-linkers. The spherical NP suspensions were biocompatible, monodisperse with average diameters of 72 nm (ideal for OA cartilage penetration), and they were stable over 6 months at 4 °C. Moreover, the NPs loaded celecoxib at higher levels than those required for the therapeutic response in arthritic joints. For these reasons, they are the first of their kind. Labeled NPs were internalized by primary human articular chondrocytes cultured from the knee joints of OA patients. The NPs reduced the concentration of inflammatory mediator prostaglandin E2 released by the primaries, an indication of retained bioactivity following NP synthesis. Similar results were observed in lipopolysaccharide-stimulated human THP-1 monocytes. The IA administration of these NPs is expected to avoid side-effects associated with oral administration of celecoxib and to maintain a high local concentration in the knee joint over a sustained period. They are now ready for evaluation by IA administration in animal models of OA.

Efficacy of a virtual reality-based cognitive interactive training program for children with traumatic brain injuries: study protocol for a parallel-group randomized controlled trial.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of disability in children. Cognitive rehabilitation for this population is critical for their long-term health outcomes. This trial aims to evaluate the efficacy of a virtual reality-based program (VICT) for training executive functions in children with TBI. METHODS: A parallel group randomized controlled trial will be conducted among up to 32 children with TBI. Children in the intervention group will receive the VICT training while children in the control group will play a comparable VR game without executive function training. Each participant will be assessed at baseline, post-intervention, and 1-month follow-up. Outcomes will include core executive functions, attention, and health-related quality of life measured by computerized tasks or standardized questionnaires. DISCUSSION: Cognitive rehabilitation is among the top healthcare needs for pediatric TBI patients. Virtual reality-based training is promising due to its versatile content, flexibility, and potential cost savings for both patients and providers. Findings of this trial will provide data on the efficacy of the VICT program on core executive functions, attention problems, and health-related quality of life and serve as the empirical foundation for future larger multi-site effectiveness trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT04526639 . Registered on August 18, 2020.

Good Vibrations Report on the DNA Quadruplex Binding of an Excited State Amplified Ruthenium Polypyridyl IR Probe.

The nitrile containing Ru(II)polypyridyl complex [Ru(phen)2(11,12-dCN-dppz)]2+ (1) is shown to act as a sensitive infrared probe of G-quadruplex (G4) structures. UV-visible absorption spectroscopy reveals enantiomer sensitive binding for the hybrid htel(K) and antiparallel htel(Na) G4s formed by the human telomer sequence d[AG3(TTAG3)3]. Time-resolved infrared (TRIR) of 1 upon 400 nm excitation indicates dominant interactions with the guanine bases in the case of Λ-1/htel(K), Δ-1/htel(K), and Λ-1/htel(Na) binding, whereas Δ-1/htel(Na) binding is associated with interactions with thymine and adenine bases in the loop. The intense nitrile transient at 2232 cm-1 undergoes a linear shift to lower frequency as the solution hydrogen bonding environment decreases in DMSO/water mixtures. This shift is used as a sensitive reporter of the nitrile environment within the binding pocket. The lifetime of 1 in D2O (ca. 100 ps) is found to increase upon DNA binding, and monitoring of the nitrile and ligand transients as well as the diagnostic DNA bleach bands shows that this increase is related to greater protection from the solvent environment. Molecular dynamics simulations together with binding energy calculations identify the most favorable binding site for each system, which are in excellent agreement with the observed TRIR solution study. This study shows the power of combining the environmental sensitivity of an infrared (IR) probe in its excited state with the TRIR DNA "site effect" to gain important information about the binding site of photoactive agents and points to the potential of such amplified IR probes as sensitive reporters of biological environments.

Correction: Time-resolved infra-red studies of photo-excited porphyrins in the presence of nucleic acids and in HeLa tumour cells: insights into binding site and electron transfer dynamics.

Correction for 'Time-resolved infra-red studies of photo-excited porphyrins in the presence of nucleic acids and in HeLa tumour cells: insights into binding site and electron transfer dynamics' by Páraic M. Keane et al., Phys. Chem. Chem. Phys., 2022, 24, 27524-27531, https://doi.org/10.1039/D2CP04604K.

Seeking Help for Tinnitus and Satisfaction With Healthcare Providers Including Diagnosis, Clinical Services, and Treatment: A Scoping Review.

The objective of this scoping review was to describe the extent and type of evidence related to seeking help for tinnitus and satisfaction with healthcare providers including diagnosis, services and treatments along the clinical pathway. The selection criteria were adults aged 18 and over with tinnitus who sought help and where patient satisfaction with healthcare providers was reported. Online databases MEDLINE (OvidSP), Embase (OvidSP), PsycINFO (OvidSP) and CINAHL plus (EBSCO) were searched for original studies in English. The search had no date limit. Twenty-one records were eligible for data extraction. Studies reported that the most common healthcare providers seen were general practitioners, ear, nose and throat specialists and audiologists. Depression and tinnitus severity were related to an increase in the number of times help was sought and the type of healthcare provider seen may also impact patient satisfaction. The majority of participants were unlikely to receive a referral to a specialist at the initial GP consultation. Although there is limited research in this area, help-seekers for tinnitus were generally dissatisfied and reported negative interactions with healthcare providers. However, once in a specialised tinnitus clinical setting, studies reported that most help-seekers were satisfied and had positive interactions with healthcare providers.

The use of patient-report measures and intervention strategies for children and adolescents with chronic tinnitus: a scoping review.

BACKGROUND: Chronic tinnitus during childhood/adolescence can be associated with impaired quality of life. Guidelines for managing paediatric tinnitus recommend assessment and interventions are often based upon the experiences and opinions of guideline committee members. OBJECTIVE: To examine patient response tools used for the assessment and management of childhood tinnitus and how interventions had been evaluated. DESIGN: A structured scoping review (i) identifying and critically appraising patient response measures (PRMs) assessing tinnitus in children/adolescents, and (ii) critically appraising evidence supporting reported interventions. Original papers written in English, involving paediatric participants ≤19 years, reporting (i) application of established PRMs to assess the experience of chronic tinnitus or (ii) application and evaluation of tinnitus interventions were included. STUDY SAMPLE: Papers written in English, identifying, or assessing the experience of chronic tinnitus (>3 months) as a primary complaint during childhood/adolescence in participants ≤19 years of age using a PRM and studies evaluating the application of non-pharmaceutical interventions for tinnitus in children/adolescents. RESULTS: Six studies involving the assessment of tinnitus during childhood/adolescence using a PRM were identified and evaluated. Three established (previously named, described, and published) PRMs were applied of which none were developed specifically for children/adolescents. Three behavioural tinnitus interventions and three combination intervention strategies (coupling of psychological intervention with sound enrichment) had been applied to and evaluated within paediatric populations. CONCLUSIONS: Although clinicians are seeing children/adolescents with tinnitus, they are evaluating and managing children's distress without appropriate PRMs, and little evidence exists to support clinical interventions.

G-Quadruplex Binding of an NIR Emitting Osmium Polypyridyl Probe Revealed by Solution NMR and Time-Resolved Infrared Studies.

G-quadruplexes are emerging targets in cancer research and understanding how diagnostic probes bind to DNA G-quadruplexes in solution is critical to the development of new molecular tools. In this study the binding of an enantiopure NIR emitting [Os(TAP)2 (dppz)]2+ complex to different G-quadruplex structures formed by human telomer (hTel) and cMYC sequences in solution is reported. The combination of NMR and time-resolved infrared spectroscopic techniques reveals the sensitivity of the emission response to subtle changes in the binding environment of the complex. Similar behaviour is also observed for the related complex [Os(TAP)2 (dppp2)]2+ upon quadruplex binding.

Time-resolved infra-red studies of photo-excited porphyrins in the presence of nucleic acids and in HeLa tumour cells: insights into binding site and electron transfer dynamics.

Cationic porphyrins based on the 5,10,15,20-meso-(tetrakis-4-N-methylpyridyl) core (TMPyP4) have been studied extensively over many years due to their strong interactions with a variety of nucleic acid structures, and their potential use as photodynamic therapeutic agents and telomerase inhibitors. In this paper, the interactions of metal-free TMPyP4 and Pt(II)TMPyP4 with guanine-containing nucleic acids are studied for the first time using time-resolved infrared spectroscopy (TRIR). In D2O solution (where the metal-free form exists as D2TMPyP4) both compounds yielded similar TRIR spectra (between 1450-1750 cm-1) following pulsed laser excitation in their Soret B-absorption bands. Density functional theory calculations reveal that vibrations centred on the methylpyridinium groups are responsible for the dominant feature at ca. 1640 cm-1. TRIR spectra of D2TMPyP4 or PtTMPyP4 in the presence of guanosine 5'-monophosphate (GMP), double-stranded {d(GC)5}2 or {d(CGCAAATTTGCG)}2 contain negative-going signals, 'bleaches', indicative of binding close to guanine. TRIR signals for D2TMPyP4 or PtTMPyP bound to the quadruplex-forming cMYC sequence {d(TAGGGAGGG)}2T indicate that binding occurs on the stacked guanines. For D2TMPyP4 bound to guanine-containing systems, the TRIR signal at ca. 1640 cm-1 decays on the picosecond timescale, consistent with electron transfer from guanine to the singlet excited state of D2TMPyP4, although IR marker bands for the reduced porphyrin/oxidised guanine were not observed. When PtTMPyP is incorporated into HeLa tumour cells, TRIR studies show protein binding with time-dependent ps/ns changes in the amide absorptions demonstrating TRIR's potential for studying light-activated molecular processes not only with nucleic acids in solution but also in biological cells.

Photophysical Properties and DNA Binding of Two Intercalating Osmium Polypyridyl Complexes Showing Light-Switch Effects.

The synthesis and photophysical characterization of two osmium(II) polypyridyl complexes, [Os(TAP)2dppz]2+ (1) and [Os(TAP)2dppp2]2+ (2) containing dppz (dipyrido[3,2-a:2',3'-c]phenazine) and dppp2 (pyrido[2',3':5,6]pyrazino[2,3-f][1,10]phenanthroline) intercalating ligands and TAP (1,4,5,8-tetraazaphenanthrene) ancillary ligands, are reported. The complexes exhibit complex electrochemistry with five distinct reductive redox couples, the first of which is assigned to a TAP-based process. The complexes emit in the near-IR (1 at 761 nm and 2 at 740 nm) with lifetimes of >35 ns with a low quantum yield of luminescence in aqueous solution (∼0.25%). The Δ and Λ enantiomers of 1 and 2 are found to bind to natural DNA and with AT and GC oligodeoxynucleotides with high affinities. In the presence of natural DNA, the visible absorption spectra are found to display significant hypochromic shifts, which is strongly evident for the ligand-centered π-π* dppp2 transition at 355 nm, which undergoes 46% hypochromism. The emission of both complexes increases upon DNA binding, which is observed to be sensitive to the Δ or Λ enantiomer and the DNA composition. A striking result is the sensitivity of Λ-2 to the presence of AT DNA, where a 6-fold enhancement of luminescence is observed and reflects the nature of the binding for the enantiomer and the protection from solution. Thermal denaturation studies show that both complexes are found to stabilize natural DNA. Finally, cellular studies show that the complexes are internalized by cultured mammalian cells and localize in the nucleus.

Hook, Line, and Sinker! Spectroscopic Studies of Bi-Modular Mono- and Bis-1,8-naphthalimide-Ru(bpy)3-conjugates as DNA "Light Switches".

Bi-chromophoric ruthenium polypyridyl complexes comprising one or two nitro-1,8-naphthalimide groups are shown to be effective DNA binders with off-on light switching properties. The binding to DNA was investigated using a combination of studies such as UV-visible absorption and emission titrations, thermal denaturation, and circular dichroism spectroscopy. The DNA affinity was shown to be sensitive to both the linker length and the number of naphthalimides (one vs two) contained in these systems and binding constants ranging from 106 to 107 M-1 for salmon testes DNA. The strong DNA binding is attributed to the combination of naphthalimide intercalation and the electrostatic interaction of the ruthenium complex. Large emission enhancements from the metal to ligand charge transfer (MLCT) emission arising from the metal complex were observed upon DNA binding, which was attributed to the interruption of intramolecular electron transfer quenching processes. Moving the nitro substitution from the 4-position to the 3-position is found to result in modification of the DNA binding and the resulting optical properties. The off-on light switch phenomena reported demonstrate the potential of these complexes to act as DNA probes.

Multiparametric nanoparticle-induced toxicity readouts with single cell resolution in HepG2 multicellular tumour spheroids.

The use of nanomaterials as therapeutic delivery vehicles requires their careful pre-clinical evaluation. Of particular importance in this regard is measurement of cellular toxicity, ideally assessing multiple parameters in parallel from various relevant subcellular organelles. In recent years it has become evident that in vitro monolayer-grown cells do not always accurately predict any toxicity response seen in vivo, and so there is a need for more sophisticated in vitro cell models, employing a greater depth of characterisation. In this work we present an automated high-content screening microscopy approach for quantifying nanoparticle-induced toxicity in a three-dimensional multicellular tumour spheroid (MCTS) cell model. As a proof-of-principle, we perform a comparative toxicity profile study of carboxylate- versus amine-modified polystyrene nanoparticles in HepG2 spheroids. Following treatment with these nanoparticle types, we demonstrate that several hundred spheroids, of various sizes, can be morphologically profiled in a single well using automated high-content image analysis. This provides a first level of information about spheroid health in response to nanoparticle treatment. Using a range of fluorescent reporters assessing membrane permeability, lysosome function and mitochondrial activity, we also show that nanoparticle-induced toxicity information can be obtained from individual cells with subcellular resolution. Strikingly, our work demonstrates that individual cells do not all behave in a consistent manner within a spheroid structure after exposure to nanoparticles. This highlights the need for toxicity studies to not only assess an appropriate number of spheroids, but also the importance of extracting information at the subcellular level.

Adenine Radical Cation Formation by a Ligand-Centered Excited State of an Intercalated Chromium Polypyridyl Complex Leads to Enhanced DNA Photo-oxidation.

Assessment of the DNA photo-oxidation and synthetic photocatalytic activity of chromium polypyridyl complexes is dominated by consideration of their long-lived metal-centered excited states. Here we report the participation of the excited states of [Cr(TMP)2dppz]3+ (1) (TMP = 3,4,7,8-tetramethyl-1,10-phenanthroline; dppz = dipyrido[3,2-a:2',3'-c]phenazine) in DNA photoreactions. The interactions of enantiomers of 1 with natural DNA or with oligodeoxynucleotides with varying AT content (0-100%) have been studied by steady state UV/visible absorption and luminescence spectroscopic methods, and the emission of 1 is found to be quenched in all systems. The time-resolved infrared (TRIR) and visible absorption spectra (TA) of 1 following excitation in the region between 350 to 400 nm reveal the presence of relatively long-lived dppz-centered states which eventually yield the emissive metal-centered state. The dppz-localized states are fully quenched when bound by GC base pairs and partially so in the presence of an AT base-pair system to generate purine radical cations. The sensitized formation of the adenine radical cation species (A•+T) is identified by assigning the TRIR spectra with help of DFT calculations. In natural DNA and oligodeoxynucleotides containing a mixture of AT and GC of base pairs, the observed time-resolved spectra are consistent with eventual photo-oxidation occurring predominantly at guanine through hole migration between base pairs. The combined targeting of purines leads to enhanced photo-oxidation of guanine. These results show that DNA photo-oxidation by the intercalated 1, which locates the dppz in contact with the target purines, is dominated by the LC centered excited state. This work has implications for future phototherapeutics and photocatalysis.

Prevalence of Hyperacusis and Its Relation to Health: The Busselton Healthy Ageing Study.

IMPORTANCE: The prevalence of hyperacusis and its relationship with mental and general health is unknown in a nonclinical sample. Therefore, we aimed to determine the prevalence of hyperacusis and its relation with hearing, general and mental health in a population-based study. STUDY DESIGN: Prospective population-based study. MATERIAL AND METHODS: This study uses data from the Busselton Healthy Ageing Study (BHAS). A sample of 5,107 eligible inhabitants aged 45 to 70 years completed a detailed questionnaire and a clinical assessment. A positive answer to "Do you consider yourself sensitive or intolerant to everyday sounds" was used to indicate hyperacusis. Logistic regression was used to examine the association between hearing, mental and general health factors, and hyperacusis. RESULTS: Of 5,107 participants, 775 (15.2%) reported hyperacusis. The majority of participants with hyperacusis reported an occasional effect on daily life (72.0%). Being female, older in age, having a lower income, physical or mental health difficulties, more severe hearing loss, and tinnitus were all associated with the presence of hyperacusis. Individuals who experience hearing impairment, poorer general or mental health have a higher possibility of hyperacusis having an effect on their daily life. CONCLUSIONS: In this community population-based cohort study, we found a prevalence of hyperacusis of 15.2%. Individuals with hearing loss, mental health problems, and lower physical health have a higher possibility of experiencing effects on their daily life associated with their hyperacusis. Unravelling the relationship between hyperacusis hearing, general and mental health can be of major importance for a better understanding of the condition and its consequences. LEVEL OF EVIDENCE: 2 Laryngoscope, 131:E2887-E2896, 2021.

Reducing the Impact of Tinnitus on Children and Adolescents' Lives: A Mixed-Methods Concept Mapping Study.

OBJECTIVES: To generate a conceptual framework describing what is done to reduce the impact of chronic tinnitus on the lives of children and adolescents. DESIGN: Views and experiences of 32 adults from two participant groups informed this concept mapping study: (i) a tinnitus group (adults who experienced tinnitus during childhood/adolescence, and primary carers of children/adolescents with tinnitus) and (ii) a clinicians' group (clinicians who provided care for children/adolescents with tinnitus). Participants produced statements describing what is done to reduce the impact of chronic tinnitus on the lives of children and adolescents who experience it. Through grouping and rating processes, they identified key concepts and inferred their associated benefit. RESULTS: The participants generated 102 unique statements across four concepts: (1) Education, Support, and Counselling; (2) Support from Parents and Teachers; (3) Clinical Assessments and Management; and (4) Self-Management Techniques. Many statements highlighted the need for child-friendly and patient-centred care. Adults with personal experience of childhood tinnitus tended to perceive many of the statements as more beneficial than did the clinician group. CONCLUSIONS: Although many children will develop management strategies to assist them with their tinnitus, both the adults who experienced tinnitus as children and their parents valued strategies involving clinical care, knowledge, and expertise. Participants from the tinnitus group perceived a greater degree of benefit associated with strategies from all four clusters than the clinicians' group. However, both groups perceived the greatest degree of benefit as being associated with activities and strategies within the Education, Support, and Counselling and the Clinical Assessments and Management clusters. Both groups identified that recognising the occurrence of tinnitus for children and adolescents, acknowledging the potential for associated distress, and initiating clinical care provide the nexus of effective management. Addressing the concerns and needs of parents was also perceived as valuable; hence, approaching the management of tinnitus during childhood and adolescence from a family-centred care framework is recommended.

Reflections on How Tinnitus Impacts the Lives of Children and Adolescents.

Objectives The aim of this study was to generate a conceptual framework describing which aspects of children and adolescents' lives are affected by chronic tinnitus. Design Views and experiences of 32 participants from two participant groups informed this study: (a) a tinnitus group, consisting of adults who had experienced tinnitus during childhood and/or adolescence and primary carers of children/adolescents with tinnitus, and (b) a clinicians' group, consisting of clinicians who provided care for children/adolescents with tinnitus. Participants produced statements describing aspects of children/adolescents' lives that may be affected by chronic tinnitus. Key concepts were identified through the processes of sorting the statements and rating them for degree of associated impact. Result Participants identified 118 unique aspects of the lives of children/adolescents who may be affected by chronic tinnitus. These were clustered into four concepts: (a) emotional well-being, (b) academic performances, (c) social/relationa, and (d) auditory/cognitive processing. At a group level, participants rated the impact of tinnitus as above a slight degree but below a moderate degree of impact. However, individual participant's ratings indicated a range of perceived impact for each statement. Conclusions The experience of chronic tinnitus during childhood and adolescence extends beyond the mere perception of sound. The perception of tinnitus may impact a child's emotional well-being, academic performances, social/relational, and auditory/cognitive processing. The impact of tinnitus in one aspect of a child's life may influence other aspects of their life. While at a group level, participants regarded the impact of tinnitus as "somewhat more than mild" to "less than moderate"; individual participant's ratings indicate that the impact from chronic tinnitus may be highly individual and highlighted the importance of individual assessment and management. Clinically, tinnitus management during childhood and adolescence may be improved if clinicians consider the impact and manifestation of tinnitus within each child's daily life and tailor tinnitus education and management strategies accordingly.

Tinnitus and its associations with general health, mental health and hearing loss.

BACKGROUND: A deeper knowledge of tinnitus is essential in order to better manage and treat tinnitus and its effects. Most studies to date are based on small samples and/or conducted in clinical settings. In this study we assessed the associations between tinnitus, general and mental health, hearing status and demographics in a large population cohort study. MATERIALS AND METHODS: The Busselton Healthy Aging Study recruited people born between 1946 and 1964. Data were collected between 2010 and 2015. Logistic regression was used to examine the associations between tinnitus and its effect on daily life, age, gender, hearing, self-reported mental and general health, and doctor diagnosed health conditions. RESULTS: Of 5107 participants, 1154 (22.6%) reported experiencing tinnitus. Of those, 32.4% reported that their tinnitus had an occasional effect on their daily lives, while for a further 8.9% the effect on their daily life was frequent or constant. The odds ratio for having a SF12-PCS was (OR 1.02 (95%CI 1.01-1.03). Furthermore, individuals who experience their tinnitus as having an effect on their daily life, have an increased risk of having a lower general health (OR 1.04 (95%CI 1.02-1.03)) than those without tinnitus. Higher levels of depression, anxiety and stress, as well as doctor diagnosed depression, were all significant risk factors for tinnitus. There were statistically significant worse hearing thresholds related to the presence of tinnitus. CONCLUSION: The outcomes raise the question for clinicians and researchers whether addressing the mental and general health of individuals will influence the presence or burden of tinnitus.

Porous Carbon Microparticles as Vehicles for the Intracellular Delivery of Molecules.

In this study the application of porous carbon microparticles for the transport of a sparingly soluble material into cells is demonstrated. Carbon offers an intrinsically sustainable platform material that can meet the multiple and complex requirements imposed by applications in biology and medicine. Porous carbon microparticles are attractive as they are easy to handle and manipulate and combine the chemical versatility and biocompatibility of carbon with a high surface area due to their highly porous structure. The uptake of fluorescently labeled microparticles by cancer (HeLa) and normal human embryonic Kidney (HEK 293) cells was monitored by confocal fluorescence microscopy. In this way the influence of particle size, surface functionalization and the presence of transfection agent on cellular uptake were studied. In the presence of transfection agent both large (690 nm) and small microparticles (250 nm) were readily internalized by both cell lines. However, in absence of the transfection agent the uptake was influenced by particle size and surface PEGylation with the smaller nanoparticle size being delivered. The ability of microparticles to deliver a fluorescein dye model cargo was also demonstrated in normal (HEK 293) cell line. Taken together, these results indicate the potential use of these materials as candidates for biological applications.

Reflections and perceptions of chronic tinnitus during childhood and adolescence.

OBJECTIVES: To enhance understanding of the lived experience of tinnitus during childhood/adolescence from the reflections of adults who experienced tinnitus during childhood/adolescence and the perceptions of primary carers and clinicians who care for children/adolescents who experience it. Secondly to develop a conceptual framework to better describe the experience of chronic tinnitus during childhood/adolescence and to guide approaches to assessment and management. DESIGN: Using a concept mapping approach, participants from two stakeholder groups generated statements describing what chronic tinnitus sounds and feels like to children/adolescents who experience it. Participants subsequently grouped and rated the statements to reveal key concepts. The first stakeholder group consisted of adults who had experienced chronic tinnitus as a child/adolescent and parents of children or adolescents who are experience chronic tinnitus. The second stakeholder group consisted of clinical professionals who provide care for children/adolescents experiencing chronic tinnitus. RESULTS: Participants identified 102 different descriptions of what chronic tinnitus sounds and feels like to children/adolescents, across five concepts: 1) Sounds of tinnitus; 2) Descriptions of tinnitus; 3) Perceptions of tinnitus; 4) Emotional responses to tinnitus and 5) Physical responses to tinnitus. CONCLUSIONS: The experience of chronic tinnitus during childhood/adolescence is heterogenous and multifaceted. It may involve the perception of sound, emotions and physiological sequalae. How a child/adolescent experiences their tinnitus will be influenced by the interplay between the sound they perceive, the number of accompanying senses involved and their interpretation of the sound. As well as the emotions and physical effects they experience.

Synthesis, Characterization, and Biological Profiling of Ruthenium(II)-Based 4-Nitro- and 4-Amino-1,8-naphthalimide Conjugates.

We report the synthesis, photophysical characterization, and biological evaluation of four DNA-binding ruthenium(II) polypyridyl 4-nitro- and 4-amino-1,8-naphthalimide conjugates. A meta arrangement around the ring connecting the 1,8-naphthalimide to a bipyridine ligand creates a cleft, the result of which renders the shape of the complex complementary to that of DNA. We have demonstrated that each complex exhibits water solubility and a distinctive set of photophysical properties that has allowed the nature of their interaction with DNA to be probed by various ground- and excited-state titrations. Furthermore, by varying the ancillary ligands, we also demonstrate their ability to act as DNA photocleavers, where all compounds have been found to cleave supercoiled DNA with high efficiency. Detailed cellular uptake experiments revealed that the conjugates accumulate in the cytoplasm and nucleus of HeLa cells, showing characteristic red metal-to-ligand charge-transfer emission, and also exhibit photoactivated cytotoxicity within the cells upon irradiation at 450 nm. A comparison between the meta and para arrangements of the 1,8-naphthalimide moiety relative to the Ru(II) center suggests increased DNA binding in the case of the meta arrangement; however, bipyridine-4-amino-1,8-naphthalimide conjugates appear to show superior phototoxicity in comparison to their 4-nitro derivatives.

Caught in the Loop: Binding of the [Ru(phen)2 (dppz)]2+ Light-Switch Compound to Quadruplex DNA in Solution Informed by Time-Resolved Infrared Spectroscopy.

Ultrafast time-resolved infrared (TRIR) is used to report on the binding site of the [Ru(phen)2 (dppz)]2+ "light-switch" complex with both bimolecular (Oxytricha nova telomere) and intramolecular (human telomere) guanine-quadruplex structures in both K+ and Na+ containing solutions. TRIR permits the simultaneous monitoring both of the "dark" and "bright" states of the complex and of the quadruplex nucleobase bases, the latter via a Stark effect induced by the excited state of the complex. These data are used to establish the contribution of guanine base stacking and loop interactions to the binding site of this biologically relevant DNA structure in solution. A particularly striking observation is the strong thymine signal observed for the Na+ form of the human telomere sequence, which is expected to be in the anti-parallel conformation.