Neuronale Korrelate der Tinnitussuppression mittels amplitudenmodulierter akustischer Stimulation: eine EEG-Studie

Einleitung Akustische Stimulation ist ein vielversprechender Ansatz zur kurzzeitigen Unterdrückung des chronisch subjektiven Tinnitus. In vorangegangenen Studien wurde bereits die Effektivität amplitudenmodulierter (AM) Töne im Vergleich mit unmodulierten Tönen untersucht, wobei eine etwas bessere Wirksamkeit von amplitudenmodulierten Stimuli, speziell auf der Tinnitusfrequenz beobachtet wurde. Da Tinnitus mit einer Reduktion der Alpha-Power in auditorischen Arealen des Gehirns assoziiert ist, könnte neben dem Mechanismus der residualen Inhibition zusätzlich das Entrainment der auditorischen Alpha-Oszillationen hierbei eine Rolle spiele. Diese Form der neuronalen Anpassung an einen externen Reiz wurde insbesondere für die 10 Hz AM Stimuli angenommen, da dies der Frequenz der Alphawellen (8 – 12 Hz) entspricht. Neben physikalischen Eigenschaften wurde des Weiteren ein Zusammenhang zwischen Tinnitussuppression und emotionaler Bewertung der Stimuli sowie persönlichkeits- und tinnitusbezogener Merkmale untersucht. Methoden Insgesamt nahmen 42 Patienten mit chronischem subjektivem Tinnitus an dem Experiment teil. Das Studienprotokoll beinhaltete eine Fragebogenanalyse, Audiometrie, Tinnitus Matching und die akustische Stimulation mit anschließender Bewertung der Tinnituslautstärke. Letztere erfolgte mit vier AM Tönen und einem unmodulierten Ton auf der Tinnitusfrequenz (iTin) in einer randomisierten Reihenfolge für jeweils 3 Minuten mit einer Lautstärke von 65 dB oberhalb des Sensation Levels (SL). Die AM Stimuli basierten auf Modulationsraten von 10 Hz und 23 Hz, jeweils auf der Tinnitusfrequenz (AM10 und AM23) sowie drei Oktaven tiefer (AM10deep und AM23deep). Abschließend wurden die Stimuli emotional hinsichtlich Valence und Arousal bewertet. Während der gesamten akustischen Stimulation wurde ein EEG aufgezeichnet, um neuronale Korrelate der Tinnitusunterdrückung darzustellen. Mithilfe von Varianzanalysen (ANOVA) und gepaarten T-Tests konnten Unterschiede zwischen den Stimuli hinsichtlich kurzzeitiger Tinnitussuppression sowie Änderungen der Alpha-Power identifiziert werden. Zudem wurden Pearson-Korrelationen berechnet um mögliche Prädiktoren (Tinnitusdauer, -belastung und Persönlichkeit) zu identifizieren. Ergebnisse AM10deep unterschied sich signifikant am stärksten von iTin hinsichtlich kurzzeitiger Tinnitussuppression nach der akustischen Stimulation. Zum Zeitpunkt 0 nach der akustischen Stimulation war die Tinnituslautstärke auf 75% des Ausgangwertes reduziert. AM10 wurde im Vergleich mit iTin am besten emotional in Bezug auf Valence und Arousal bewertet. Für alle fünf Stimuli resultierte eine Reduktion der Alpha-Power nach der akustischen Stimulation. Signifikante Unterschiede für den Faktor Zeit ergaben sich für AM23deep, AM10deep, iTin und AM10. Zudem zeigte sich ein signifikant negativer Zusammenhang zwischen der Differenz der Alpha-Power vor und nach der Stimulation und der Tinnituslautstärke für die Stimuli AM23 und AM10deep. Hinsichtlich möglicher Prädiktoren korrelierten sowohl Tinnitusdauer als auch Tinnitusbelastung positiv mit der Tinnituslautstärke nach der akustischen Stimulation. Diskussion Entgegen vorheriger Akustikstudien mit amplitudenmodulierten Tönen, erzielten die Stimuli im Tieftonbereich, insbesondere AM10deep, bessere kurzzeitige Suppressionseffekte der Tinnituslautstärke als die Töne auf der Tinnitusfrequenz. Generell wurden die Stimuli mit einer Modulationsrate von 10 Hz emotional am besten bewertet. Hinsichtlich guter Verträglichkeit und Wirksamkeit bieten diese Erkenntnisse neue Ansätze für weitere Studien auf diesem Gebiet. Die im EEG aufgezeichnete Reduktion der Alpha-Power nach der akustischen Stimulation für alle fünf Stimuli ist als physiologische Reaktion auf einen akustischen Reiz, im Sinne einer Desynchronisation, zu interpretieren. Der negative Zusammen-hang zwischen der Differenz der Alpha-Power vor und nach der Stimulation und der Tinnituslautstärke könnte Hinweise auf eine zunehmende Variabilität der Alpha-Aktivität geben. Die Studie liefert somit weitere Einblicke in die neuronalen Mechanismen der Verarbeitung akustischer Reize im Alpha-Frequenzbereich. Da jedoch kein direkter Zusammenhang zwischen der Reduktion der Tinnituslautstärke und einer Zunahme der Alpha-Power gezeigt werden konnte, müssen weitere Studien mit bildgebenden Verfahren wie Magnetenzephalographie (MEG) oder funktioneller Magnetresonanz-tomographie (fMRT) durchgeführt werden. Als mögliche Prädiktoren für die Wirksamkeit von akustischen Stimulationsverfahren könnten zukünftig Tinnitusdauer und Tinnitusbelastung mit einbezogen werden

The first report on periphytic diatoms on artificial and natural substrate in the karstic spring Bunica, Bosnia and Herzegovina

This study presents investigations of the periphytic diatoms on artificial (glass slides) and natural substrates in the karstic, limnocrene spring of Bunica situated in the south of Bosnia and Herzegovina. Investigations were performed in summer 2010. Samples were collected every seven days for eight weeks. Physical and chemical characteristics of water, temperature, oxygen saturation, dissolved oxygen, electric conductivity and nutrients as well as flow velocity at sample site, were measured simultaneously with each sampling. Physical and chemical characteristics showed low temperature oscillations, good aeration and oligotrophic conditions. In general, greater diatom diversity was noted on natural substrate. A total of 104 diatom species were found on natural substrate and 82 on glass slides. The best represented genera on both types of substrate were Gomphonema and Navicula (each with eight species), Nitzschia (with six species), and Cocconeis (with five species). Achnanthidium exiguum, Achnanthidium minutissimum, Amphora pediculus, Cymbopleura amphicephala and Surirella minuta were recorded in all samples of natural substrate and Gomphonema minutum in artificial substrate samples

Sinteza konjugata fenoprofena i gemfibrozila s kopolimerom stirena i maleinske kiseline

Two types of polymer-drug conjugates were synthesized starting from styrene-maleic acid anhydride copolymer (SMA). Fenoprofen and gemfibrozil were chosen as model drugs because of their short plasma half lives. Both drugs were first converted to their 2-aminoethylamides, which possess free amino groups capable of reacting with SMA anhydride rings. By modifying the degree and type of substitution, lipophilic and hydrophilic conjugates were obtained. Drug loading in the conjugates was between 17 and 47%.U radu je opisana sinteza polimer-lijek konjugata polazeći od kopolimera stirena i anhidrida maleinske kiseline (SMA) i fenoprofena, odnosno gemfibrozila, ljekovitih tvari s kratkim vremenom zadržavanja u plazmi. Fenoprofen i gemfibrozil su prvo prevedeni u 2-aminoetilamide, koji su zbog slobodne amino skupine mogli reagirati s anhidridnim prstenovima u SMA. Modifikacijom tipa i vrste supstitucije pripravljeni su lipofilni i hidrofilni konjugati. Udio vezanog lijeka u konjugatima bio je između 17 and 47%

Biodiversity and seasonal distribution of benthic diatom assemblages as an indicator of water quality of small karstic river in Bosnia and Herzegovina

The aims of this paper were to describe seasonal changes in the qualitative and quantitative composition of diatom taxa and the potential application of benthic diatoms for ecological status evaluation. Diatom indices (IPS and TI) were calculated from data from three different locations along a longitudinal profile of the Bunica, a small karstic river in Bosnia and Herzegovina. A total of 147 taxa were recorded in 12 samples. The most common taxa were Meridion circulare (Greville) C.Agardh and Ulnaria ulna (Nitzsch) Compère. Physical and chemical analyses showed low concentrations of nutrients, good oxygenation, typical pH for carbonate bed/origin and generally oligotrophic conditions and high ecological status. All sites had similar physico-chemical conditions and there were only few seasonal differences. Ordination of the diatom data showed that samples showed neither longitudinal nor seasonal patterns. Median value for IPS (16.8) and for TI (7.3) can be possible ‘‘expected’’ values for ecological status assessment for small karstic rivers in the Mediterranean region. We propose the use of the phytobenthos Intercalibration Common Metric (pICM - an index that combines the IPS and TI) as a national metric for countries developing WFD diatom methods at a late stage. One situation is described, and a solution, which is potentially transferable to other locations in Bosnia and Herzegovina and also to other countries facing similar challenges

In vitro dissolution/release methods for mucosal delivery systems

In vitro dissolution/release tests are an indispensable tool in the drug product development, its quality control and the regulatory approval process. Mucosal drug delivery systems are designed to provide both local and systemic drug action following ocular, nasal, oromucosal, vaginal or rectal administration. They exhibit significant differences in formulation design, physicochemical characteristics and drug release properties. Therefore it is not possible to devise a single method which would be suitable for release testing of such versatile and complex dosage forms. Different apparatuses and techniques for in vitro release testing for mucosal delivery systems considering the specific conditions at the administration site are described. In general, compendial apparatuses and methods should be used as a first approach in method development when applicable. However, to assure adequate simulation of conditions in vivo, novel biorelevant in vitro dissolution/release methods should be developed. Equipment set up, the selection of dissolution media and volume, membrane type, agitation speed, temperature, and assay analysis technique need to be carefully defined based on mucosal drug delivery system characteristics. All those parameters depend on the delivery system and physiological conditions at the site of application and may vary in a wide range, which will be discussed in details

In vitro dissolution/release methods for mucosal delivery systems

In vitro dissolution/release tests are an indispensable tool in the drug product development, its quality control and the regulatory approval process. Mucosal drug delivery systems are designed to provide both local and systemic drug action following ocular, nasal, oromucosal, vaginal or rectal administration. They exhibit significant differences in formulation design, physicochemical characteristics and drug release properties. Therefore it is not possible to devise a single method which would be suitable for release testing of such versatile and complex dosage forms. Different apparatuses and techniques for in vitro release testing for mucosal delivery systems considering the specific conditions at the administration site are described. In general, compendial apparatuses and methods should be used as a first approach in method development when applicable. However, to assure adequate simulation of conditions in vivo, novel biorelevant in vitro dissolution/release methods should be developed. Equipment set up, the selection of dissolution media and volume, membrane type, agitation speed, temperature, and assay analysis technique need to be carefully defined based on mucosal drug delivery system characteristics. All those parameters depend on the delivery system and physiological conditions at the site of application and may vary in a wide range, which will be discussed in details

D-Optimal Design in the Development of Rheologically Improved In Situ Forming Ophthalmic Gel

In situ forming ophthalmic gels need to be fine tuned considering all the biopharmaceutical challenges of the front of the eye in order to increase drug residence time at the application site resulting in its improved bioavailability and efficacy. The aim of this study was to develop in situ forming ophthalmic poloxamer P407/poloxamer P188/chitosan gel fine tuned in terms of polymer content, temperature of gelation, and viscosity. Minimizing the total polymer content while retaining the advantageous rheological properties has been achieved by means of D-optimal statistical design. The optimal in situ forming gel was selected based on minimal polymer content (P407, P188, and chitosan concentration of 14.2%, 1.7%, and 0.25% w/w, respectively), favorable rheological characteristics, and in vitro resistance to tear dilution. The optimal in situ forming gel was proved to be robust against entrapment of active pharmaceutical ingredients making it a suitable platform for ophthalmic delivery of active pharmaceutical ingredients with diverse physicochemical properties

A Controlled Trial of Isoniazid in Persons with Anergy and Human Immunodeficiency Virus Infection Who Are at High Risk for Tuberculosis

BACKGROUND Patients with human immunodeficiency virus (HIV) infection and latent tuberculosis are at substantial risk for the development of active tuberculosis. As a public health measure, prophylactic treatment with isoniazid has been suggested for HIV-infected persons who have anergy and are in groups with a high prevalence of tuberculosis. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial of six months of prophylactic isoniazid treatment in HIV-infected patients with anergy who have risk factors for tuberculosis infection. The primary end point was culture-confirmed tuberculosis. RESULTS The study was conducted from November 1991 through June 1996. Over 90 percent of the patients had two or more risk factors for tuberculosis infection, and nearly 75 percent of patients were from greater New York City. After a mean follow-up of 33 months, tuberculosis was diagnosed in only 6 of 257 patients in the placebo group and 3 of 260 patients in the isoniazid group (risk ratio, 0.48; 95 percent confidence interval, 0.12 to 1.91; P=0.30). There were no significant differences between the two groups with regard to death, death or the progression of HIV disease, or adverse events. CONCLUSIONS Even in HIV-infected patients with anergy and multiple risk factors for latent tuberculosis infection, the rate of development of active tuberculosis is low. This finding does not support the use of isoniazid prophylaxis in high-risk patients with HIV infection and anergy unless they have been exposed to active tuberculosis

ESVM guidelines:the diagnosis and management of Raynaud's phenomenon

Regarding the clinical diagnosis of Raynaud's phenomenon and its associated conditions, investigations and treatment are substantial, and yet no international consensus has been published regarding the medical management of patients presenting with this condition. Most knowledge on this topic derives from epidemiological surveys and observational studies; few randomized studies are available, almost all relating to drug treatment, and thus these guidelines were developed as an expert consensus document to aid in the diagnosis and management of Raynaud's phenomenon. This consensus document starts with a clarification about the definition and terminology of Raynaud's phenomenon and covers the differential and aetiological diagnoses as well as the symptomatic treatment

European position paper on rhinosinusitis and nasal polyps 2020

The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings. EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise . The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included