Analysis of mental disorders in tinnitus patients performed with Composite International Diagnostic Interview.

PURPOSE: Known association between tinnitus and psychological distress prompted us to examine patients with chronic tinnitus by using the Composite International Diagnostic Interview (CIDI), which is a standardized and reliable method used for the diagnosis of mental disorders. METHODS: One hundred patients with chronic tinnitus admitted to the Tinnitus Center, Charité-Universitätsmedizin Berlin, were included in this study. Data were collected between February 2008 and February 2009. Besides CIDI, the Tinnitus Questionnaire according to Goebel and Hiller, the Hospital Anxiety Depression Scale, and the General Anxiety Disorder-7 were used. RESULTS: Using CIDI, we have identified one or more mental disorders in 46 tinnitus patients. In that group, we found persistent affective disorders (37 %), anxiety disorders (32 %), and somatoform disorders (27 %). Those patients who had affective or anxiety disorders were more distressed by tinnitus and were more anxious and more depressed than tinnitus patients without mental disorders. Psychological impairment positively correlated with tinnitus distress: Patients with decompensated tinnitus had significantly more affective and anxiety disorders than patients with compensated tinnitus. CONCLUSIONS: In the present study, we have detected a high rate (almost half of the cases) of psychological disorders occurring in patients with chronic tinnitus. The patients diagnosed with psychological disorders were predominantly affected by affective and anxiety disorders. Psychological disorders were associated with severity of tinnitus distress. Our findings imply a need for routine comprehensive screening of mental disorders in patients with chronic tinnitus.

Psychological comorbidity in patients with chronic tinnitus: analysis and comparison with chronic pain, asthma or atopic dermatitis patients.

PURPOSE: To determine the prevalence and severity of psychological comorbidity in patients with chronic tinnitus in comparison with other chronic illnesses, namely chronic pain, chronic asthma and atopic dermatitis. METHODS: Psychological diagnoses were done according to ICD-10 Chapter V(F). Subjective impairment was evaluated using 5 psychometric questionnaires: tinnitus questionnaire, Berlin mood questionnaire, sense of coherence (SOC-L9) and perceived stress questionnaire. Sleep disturbance was measured by the subdomain 'exhaustion' of the Giessen physical complaints inventory. RESULTS: Somatoform or affective disorders were most frequent in all disease groups. Patients with chronic tinnitus had a stronger SOC and better subjective mood, stronger commitment, and less anger and anxious depression than the patients with chronic pain, chronic asthma or atopic dermatitis. However, in patients with higher tinnitus annoyance, psychological comorbidity was similar to that found in patients with other chronic diseases. CONCLUSIONS: Besides collecting medical and social history, special psychometric instruments should be used for the diagnosis of tinnitus patients. Based on relative high frequency of psychological comorbidity, we recommend interdisciplinary cooperation between otorhinolaryngologists and other specialists (psychosomatic medicine, psychology or psychiatry) during the treatment of tinnitus patients, especially when high degree of tinnitus annoyance is involved.

[Psychometric instruments for the diagnosis of tinnitus]. / Psychometrische Testverfahren in der Tinnitusdiagnostik.

Tinnitus is a very complex phenomenon with various mechanisms of origin. Multimodal and interdisciplinary treatment is the most effective form of treatment for patients with chronic tinnitus. In order to assess existing comorbidity in tinnitus patients as well as to treat the patients individually, a comprehensive and differentiated diagnosis is needed. Since standardized guidelines for the use of relevant instruments in the diagnosis of tinnitus have been lacking hitherto, we present here psychometric questionnaires which have already been used effectively in the research, diagnosis and therapy of tinnitus in the present article. The questionnaires measure the severity of tinnitus, depression and anxiety, the perceived stress, personal resources as well as the quality of life of patients.

[Molecular biological aspects of neuroplasticity: approaches for treating tinnitus and hearing disorders]. / Molekularbiologische Aspekte der Neuroplastizität: Ansätze für die Therapie bei Tinnitus und Hörstörungen.

Peripheral and central structures are involved in the onset of tinnitus. Neuronal plasticity is of special importance for the occurrence of central tinnitus and its persistent form. Neuronal plasticity is the ability of the brain to adapt its own structure (synapses, nerve cells, or even whole areas of the brain) and its organization to modified biological requirements. Neuroplasticity is an ongoing dynamic process. Generally speaking, there are two types of plasticity: synaptic and cortical. Cortical plasticity involves activity-dependent changes in size, connectivity, or in the activation pattern of cortical networks. Synaptic plasticity refers to the activity-dependent change in the strength of synaptic transmission and can affect both the morphology and physiology of the synapse. The stimulation of afferent fibers leads to long-lasting changes in synaptic transmission. This phenomenon is called long-term potentiation (LTP) or long-term depression (LTD). From the perspective of molecular biology, synaptic plasticity is of particular importance for the development of tinnitus and its persistence. Ultimately, the damage to the hair cells, auditory nerve, and excitotoxicity results in an imbalance between LTP and LTD and thus in changes of synaptic plasticity. After excessive acoustic stimulation, LTP can be induced by the increase of afferent inputs, whereas decreased afferent inputs generate LTD. The imbalance between LTP and LTD leads to changes in gene expression and involves changes in neurotransmission, in the expression of the receptors, ion channels, regulatory enzymes, and in direct changes on the synapses. This causes an increase of activity on the cellular level. As a result, the imbalance can lead to hyperactivity in the dorsal cochlear nucleus, inferior colliculus, and in the auditory cortex and, later on, to changes in cortical plasticity leading to tinnitus.

[The significance of stress: its role in the auditory system and the pathogenesis of tinnitus]. / Bedeutung von Stress : Seine Rolle im auditorischen System und bei der Tinnitusentstehung.

Emotional stress is often associated with auditory phenomena such as hyperacusis, tinnitus, Ménière's disease and vertigo. Stress develops as a result of a person's attempts to come to terms with the increased or unexpected demands of his or her environment. Stress serves to protect one from physical danger and to temporarily increase one's performance in order to increase the probability of survival. Sleep and appetite are particularly reduced, while anxiety increases. The mental changes induced by stress may contribute to the onset or exacerbation of tinnitus. The following links exist between the auditory and stress systems: the limbic system, which regulates instinctive behavior and emotions, is linked to the auditory system via the medial geniculate body (amygdala). The hypothalamus, which is the integrative center of the endocrine and autonomic systems, is linked to the auditory system via the inferior colliculus. The reticular system, which is focused on the behavior pattern of attention and excitement, projects serotonergic fibers to all pathways of the auditory system, ranging from the cochlea to the auditory cortex.

[Integrated intensive treatment of tinnitus: decrease of the tinnitus-related distress during a one-year follow-up study]. / Integrierte Tinnitusintensivbehandlung: Verringerung der tinnitusbedingten Belastung während einer 1-Jahres-Katamnese.

AIM OF THE STUDY: The therapy of the chronic tinnitus is aimed at improving the way patients cope with their tinnitus and at reducing the tinnitus-related distress. The present study investigated the changes of psychometric parameters that occurred in patients with chronic tinnitus after 7-days outpatient multidisciplinary therapy. The changes were monitored for up to 1 year in order to evaluate the long-term efficiency. METHODS: Main emphasis of the intensive tinnitus therapy applied was placed on tinnitus habituation and on teaching the patients how to apply coping strategies. The main elements of the multimodal concept included progressive muscle relaxation according to Jacobson, physiotherapy, educative seminars, training of selective attention and, lastly, the change of judgment, attitude and behaviour towards tinnitus. Psychometric parameters and tinnitus-related distress were assessed prior to and after the therapy (at 3, 6 and 12 months) using the tinnitus questionnaire (TQ) according to Goebel and Hiller. Furthermore, subjects waiting for therapy (waiting list) were recruited to the control group and compared with the therapy group which had received therapy 3 months earlier. RESULTS: The therapy group showed a significant reduction of the TQ total score after 3 months as compared to the control group. Moreover, we observed a long-term, progressive positive outcome during the one-year follow-up. The TQ total score was reduced by 10.9 points. There was an obvious decrease of the emotional and cognitive distress as well as of the intrusiveness of tinnitus, as per evaluation of TQ subscales. CONCLUSIONS: The outpatient intensive multidisciplinary tinnitus therapy with long-term aftercare has proved to be an effective method in the treatment of patients with chronic tinnitus. The outpatient setting enables the instant implementation of strategies learned during therapy in the patients' everyday life.

Differential vulnerability of outer and inner hair cells during and after oxygen-glucose deprivation in organotypic cultures of newborn rats.

Ischemia can contribute to the inner ear pathology and hearing loss. To determine the susceptibility of inner and outer hair cells (IHCs/OHCs) to ischemic and post-ischemic period, we used organotypic cultures of the organ of Corti isolated from P3 rats as an in vitro model of inner ear ischemia (oxygen-glucose deprivation, OGD). We identified the hair cells (HCs) by phalloidin staining. The cells with damaged cellular membrane integrity were identified by propidium iodide (PI)-exclusion assay. The cells with fragmented chromosomal DNA were detected by TUNEL assay. Organotypic cultures were subjected to a mild (3 h duration) or severe (4 h duration) OGD, followed by a recovery period of 21 h and 20 h, respectively. Mild OGD induced a loss of 10-20% HCs, whereas severe OGD induced loss of 35% HCs. We confirmed that OHCs are less vulnerable to OGD than IHCs. Of all missing OHCs, 80-90% was lost during the OGD period and 10-20% during the recovery period. In contrast, the loss of IHCs was equal during both experimental periods. The OGD period was mainly associated with PI-positive nuclei. TUNEL-positive nuclei were a minor fraction during the OGD period and increased during the recovery period, indicating the progression of DNA fragmentation. Our results implicate a differential susceptibility of IHCs and OHCs during and after ischemia-like insult, which may be of therapeutic consequence.

Expression of erythropoietin and angiogenic growth factors following inner ear injury of newborn rats.

Recently we have demonstrated that recombinant human erythropoietin (EPO) protects neurosensory hair cells in the organotypic culture of the organ of Corti by reducing apoptosis and necrosis. In the present study, we tested the hypothesis that EPO may be involved in reparative angiogenesis. We analyzed in parallel the endogenous erythropoietin (Epo) mRNA expression and that of Epo receptor (Epor) and of genes associated with angiogenesis in the organ of Corti, the modiolus and the stria vascularis using real time reverse transcription polymerase chain reaction and microarray. We compared the expression levels of freshly prepared tissue (control) and tissue cultured for 24 h under normoxia or hypoxia. The basal expression of Epo- and Epor mRNA in controls of all regions was very low. However, after 24 h in culture, a 20-100 fold increase of these two transcripts was measured. In culture, the vascular endothelial growth factor and the Cxcr4 (the receptor for the stromal cell-derived factor-1, Sdf-1) mRNA levels, were found to be increased and the Sdf-1 mRNA level to be decreased. Changes in mRNA expression occurred in all pathways activated in non-erythroid cells by the application of EPO (phosphoinositide 3-kinase/serine-threonine protein kinase B, Janus-type protein tyrosine kinase 2/signal transducer and activator of transcription 3, and the mitogen activated protein kinase). These data suggest that the neuroprotective effect of EPO may include at least two molecular events, the decrease of hair cell death rate and the induction of angiogenic genes.

[Pathogenesis and treatment of presbyacusis. Current status and future perspectives]. / Die Entstehung und Behandlung der Presbyakusis. Heutiger Stand und Perspektiven für die Zukunft.

Factors responsible for presbyacusis include physiological ageing processes as well as endogenous or exogenous causes. In the industrial countries, two main exogenous causes are exposure to loud noise and obesity. Pathomechanisms contributing to presbyacusis are hypoxia/ischemia, reactive species formation and oxidative stress, apoptotic and necrotic death of hair cells and spiral ganglion cells as well as inherited and acquired mutations in the mitochondrial DNA. Important for the successful treatment of presbyacusis is a timely fitting of hearing aids on both ears to improve communication and provide the auditory system with acoustic information. Using the hearing aids will also elevate the detection threshold of an existing tinnitus signal. At present, several therapeutic strategies based on pharmacological intervention are under discussion. The application of antioxidants or caloric restriction are considered to prevent or reduce oxidative stress-induced damage. Animal experiments evidenced that superoxide dismutase 2 (SOD2) strongly decreases in age; thus, a further approach may be the overexpression or modulation of the SOD2 within the cochlea. Adenoviral-mediated gene transfer technology would be a tempting approach to address this type of therapy. Finally, hair cell regeneration could be a possible treatment of presbyacusis in the future.

[Chronic tinnitus and craniomandibular disorders. Effectiveness of functional therapy on perceived tinnitus distress]. / Chronischer Tinnitus und kraniomandibuläre Dysfunktionen. Einfluss funktionstherapeutischer Massnahmen auf die Tinnitusbelastung.

BACKGROUND: Whether the co-occurrence of signs and symptoms of a craniomandibular disorder (CMD) and chronic tinnitus are coincidental or causal is controversial. Therefore, the effects of splint therapy and self-therapy on perceived tinnitus were evaluated. PATIENTS AND METHODS: Fifty-nine patients with chronic tinnitus were divided into three groups. In a cross-over design, two groups received the two different treatments and were compared with a control group. All patients received the initial basic tinnitus therapy. RESULTS: No significant correlation was established between the groups receiving treatment and the control group that would validate a link between tinnitus and CMD. CONCLUSION: The results of this study suggest a coincidental relationship between the two complexes of symptoms.

[Topical immunomodulation. A milestone for the treatment of therapy-resistant noninfectious chronic external otitis?]. / Topische Immunmodulation. Ein Meilenstein in der Behandlung der therapieresistenten nichtinfektiösen chronischen Otitis externa?

BACKGROUND: Recurrent exacerbation of chronic external otitis represents a special challenge for the attending physician. The goal of our study was to evaluate the effectiveness of novel topical immunomodulators acting through an anti-inflammatory, nonsteroidal mechanism. PATIENTS AND METHODS: In a prospective study, in 33 patients an ear wick containing tacrolimus ointment (Protopic 0.1%) was inserted every 2-3 days. Altogether, the wick was changed three times. Therapeutic outcomes were assessed by reexaminations, video-otoscopy, and a standardized findings sheet. RESULTS: Twenty-eight patients showed significant improvement of clinical symptoms, with 13 of them showing complete healing (follow-up 10-22 months). Relapses (15 cases) were associated with significantly extended symptom-free intervals and reduced numbers of further recurrent episodes. CONCLUSIONS: Because of the safe and successful anti-inflammatory effects, topical immunomodulators represent a new alternative in chronic inflammatory stages of otherwise therapy-resistant external otitis.

Effects of SERCA and PMCA inhibitors on the survival of rat cochlear hair cells during ischemia in vitro.

An important mechanism underlying cochlear hair cell (HC) susceptibility to hypoxia/ischemia is the influx of Ca(2+). Two main ATP-dependent mechanisms contribute to maintaining low Ca(2+) levels: uptake of Ca(2+) into intracellular stores via smooth endoplasmic reticulum calcium ATPase (SERCA) and extrusion of Ca(2+) via plasma membrane calcium ATPase (PMCA). The effects of the SERCA inhibitors thapsigargin (10 nM-10 microM) and cyclopiazonic acid (CPA; 10-50 microM) and of the PMCA blockers eosin (1.5-10 microM) and o-vanadate (1-5 mM) on inner and outer hair cells (IHCs/OHCs) were examined in normoxia and ischemia using an in vitro model of the newborn rat cochlea. Exposure of the cultures to ischemia resulted in a significant loss of HCs. Thapsigargin and CPA had no effect. Eosin decreased the numbers of IHCs and OHCs by up to 25 % in normoxia and significantly aggravated the ischemia-induced damage to IHCs at 5 and 10 microM and to OHCs at 10 microM. o-Vanadate had no effect on IHC and OHC counts in normoxia, but aggravated the ischemia-induced HC loss in a dose-dependent manner. The effects of eosin and o-vanadate indicate that PMCA has an important role to play in protecting the HCs from ischemic cell death.

[The role of cochlear neurotransmitters in tinnitus]. / Die Rolle der kochleären Neurotransmitter in Bezug auf Tinnitus.

Pathologic changes in the cochlear neurotransmission, e.g. as a result of intensive noise exposure or ototoxic drugs, can be a factor in the development of tinnitus. The efficiency of inhibitory and excitatory neurotransmitters may then be modulated at the switching points. Glutamate is the most important afferent neurotransmitter within the inner ear. A massive glutamate release induced by cochlear damage may result in excitotoxicity and irrevocable cell death. Efferent cochlear neurotransmitters include dopamine, gamma aminobutyric acid (GABA), acetylcholine (ACH) and serotonin. Dopamine and GABA are inhibitory transmitters that may protect the cochlea from excitotoxicity. ACH, like GABA, reduces the stiffness of the outer hair cells and increases their motility. Serotonin is a neuromodulator of the cholinergic and GABAergic innervation within the cochlea and can inhibit glutamatergic impulses. Our understanding of neurotransmission in the cochlea has been extended by advances in molecular biology, which has given rise to new approaches in the treatment of tinnitus. As there are several types of tinnitus, differing in aetiology and development, our present challenge is to achieve precise identification of the cause in individual cases of tinnitus.

[The role of stress in the pathogenesis of tinnitus and in the ability to cope with it]. / Stress bei der Tinnitusentstehung und -verarbeitung.

Besides the impairment of somatic functions, other factors including stress, and psychological and social characteristics are known to be important factors in the pathogenesis of tinnitus and the ability to cope with it. Existing coping strategies and psychosocial factors may have an influence on the degree of stress perceived through tinnitus. In the case of missing habituation, serious psychological, neurological and immunological responses to tinnitus are possible. In order to reduce the cognitive and emotional tinnitus-distress associated with this, there should be a focus on providing functional coping strategies combined with cognitive behavioural elements.

[Increasing incidence of wasp stings in otorhinolaryngological practice]. / Zunahme der Inzidenz von Wespenstichen im HNO-Bereich.

BACKGROUND: Wasp sting injuries can be lethal due to generalized reactions and edematous obstruction of the upper respiratory system. Due to media reports and our own observations, the consequences of the 2004 "plague of wasps" should be examined for the ear, nose, and throat (ENT) region. PATIENTS AND METHODS: Wasp sting injuries treated during the years 2002 to 2004 were evaluated in a retrospective study with respect to frequency, localization, therapy, occurrence of allergic reactions, and other complications. RESULTS: In 2002 to 2004, the number of patients with wasp sting injuries tripled. The occurrence of stings in the ENT region increased from 20% to more than 40%, with a strong rise in enoral and endolaryngeal stings after accidental swallowing or inhalation of wasps. The medical treatments employed proved the existence of sufficient therapeutic strategies. CONCLUSIONS: The treatments demonstrate a clear increase in wasp sting injuries in the year 2004. The main climatic cause was the European record summer of 2003, in which wasps multiplied.

[Influence of ischemia/hypoxia on the HIF-1 activity and expression of hypoxia-dependent genes in the cochlea of the newborn rat]. / Einfluss von Ischämie/Hypoxie auf die HIF-1-Aktivität und Expression von hypoxieabhängigen Genen in der Kochlea der neugeborenen Ratte.

BACKGROUND: Transcription factor HIF-1 (hypoxia-inducible factor-1) regulates the expression of genes which are involved in glucose supply, growth, metabolism, redox reactions and blood supply. Hypoxia and ischemia play an important role in the pathogenesis of tinnitus and hearing loss. Therefore, HIF-1 activity and the expression of HIF-1 dependent genes in the cochlea were examined under ischemic and hypoxic conditions. MATERIAL AND METHODS: For the HIF-1 analysis, single-cell cultures of the organ of Corti (OC), stria vascularis (SV) and modiolus (MOD) were used. mRNA expression was analyzed in the organotypic culture using a microarray technique (RN U34-chip, Affymetrix). RESULTS: Ischemia (hypoxia without glucose) and pure hypoxia increase the HIF-1 activity identically, with the highest increase found in MOD and OC. The HIF-1 alpha mRNA levels were found to be higher in SV than in the OC and MOD. During culturing, there is a clear increase in HIF-1 alpha mRNA and the expression of a number of HIF-1 dependent genes, such as Gapdh/glyceraldehyde-3-phosphate dehydrogenase, Slc2a1/solute carrier family 2 (facilitated glucose transporter), member 1, Tf/transferrin and Tfrc/transferrin receptor, in all three regions. In SV, MOD and OC, increase in the expression of Hmox1/hemoxygenase 1, Nos2/nitric oxide synthase, inducible and Tfrc is particularly high. Hypoxia (5 h) results in an increased expression of Igf2/Insulin-like growth factor 2. CONCLUSION: The present data underline the contribution of radical forming processes to the pathogenesis of inner ear diseases. For experimental research, it is important to note that organotypic culture may be coupled with hypoxia.

[Pharmacotherapy in acute tinnitis. The special role of hypoxia and ischemia in the pathogenesis of tinnitis]. / Pharmakotherapie des akuten Tinnitus. Unter besonderer Berücksichtigung der Rolle von Hypoxie und Ischämie bei der Tinnitusentstehung.

Hypoxia/ischemia may play an important role in the pathogenesis of sensorineural tinnitus due to the characteristics of the cochlear blood supply. In addition, hypoxia modulates molecular processes both in the acute and chronic forms of tinnitus. Transcription factor HIF-1 (hypoxia-inducible factor) may play a key role in the cells' adaptation to hypoxia and ischemia, while under hypoxic/ischemic conditions, HIF-1 induces changes in the gene expression which may contribute to the remodeling of particular structures within the cochlea. Disturbances in the cochlear blood supply may result in membrane changes, perineural edema, inflammation, disturbances in ion homeostasis and in the formation of reactive oxygen species. Thus, the pharmacotherapy of acute tinnitus may be aimed at the improvement of cochlear blood supply and the prevention of acute processes leading to cell damage. Pharmacotherapies with colloidal plasma substitutes, vasodilators, calcium antagonists, procaine, and cortisone have been described in the literature and are discussed here. Many of the pharmacological treatments have not been validated in double blind studies. Although it is impossible to deduce the cause of tinnitus from a drug's efficiency, there is some evidence that it can be effectively suppressed by improving blood supply, at least at certain stages. The aim is to achieve an improved pharmacotherapy by means of sophisticated diagnostic instruments for classifying particular types of tinnitus.

[Integrated intensive treatment of tinnitus: method and initial results]. / Integrierte Tinnitusintensivbehandlung: Konzept und erste praktische Erfahrungen.

In recent years, no major advances have been made in understanding the mechanisms underlying the development of tinnitus. Hence, the present therapeutic strategies aim at decoupling the subconscious from the perception of tinnitus. Mindful of the lessons drawn from existing tinnitus retraining and desensitisation therapies, a new integrated day hospital strategy of treatment lasting 7-14 days has been developed at the Charité Hospital and is presented in the present paper. The strategy for treating tinnitus in the proximity of patient domicile is designed for patients who feel disturbed in their world of perception and their efficiency due to tinnitus and give evidence of mental and physical strain. In view of the etiologically non-uniform and multiple events connected with tinnitus, consideration was also given to the fact that somatic and psychosocial factors are equally involved. Therefore, therapy should aim at diagnosing and therapeutically influencing those psychosocial factors that reduce the hearing impression to such an extent that the affected persons suffer from strain. The first results of therapy-dependent changes of 46 patients suffering from chronic tinnitus are presented. The data were evaluated before and after 7 days of treatment and 6 months after the end of treatment. Immediately after the treatment, the scores of both the tinnitus questionnaire (Goebel and Hiller) and the subscales improved significantly. These results were maintained during the 6-month post-treatment period and even improved.

Absence of BRAF mutations in UV-protected mucosal melanomas.

BACKGROUND: Mutations in BRAF have recently been identified in a significant percentage of primary and metastatic cutaneous malignant melanomas. As ultraviolet (UV) exposure may play a role in the development of cutaneous melanoma lesions with BRAF mutations, BRAF mutation frequency in melanomas arising in sites protected from sun exposure may be lower than those from sun-exposed areas. Thus, we determined the BRAF mutation frequency in a panel of 13 mucosal melanomas and compared those data with data from all currently published series of cutaneous melanomas. METHODS: BRAF exon 15 DNA from 13 archival primary mucosal melanomas (eight vulvar, four anorectal, and one laryngeal) was sequenced using intron-based primers. As archival DNA occasionally produces poor-quality template, results were confirmed with a TspRI restriction fragment length polymorphism (RFLP) that distinguishes wild-type BRAF from the common mutant form V599E. A binomial test was used to compare the mutation frequency in the mucosal melanomas with the published mutation frequency in cutaneous melanomas. RESULTS: None of the 13 mucosal melanomas in this series had an exon 15 BRAF mutation, as compared to 54/165 (33%) primary cutaneous melanomas with BRAF mutations in a compilation of all current published studies (p = 0.006). DISCUSSION: These data suggest that UV exposure, plays a role in the genesis of BRAF mutations in cutaneous melanoma, despite the absence of the characteristic C>T or CC>TT mutation signature associated with UV exposure, and suggests mechanisms other than pyrimidine dimer formation are important in UV-induced mutagenesis.

Antiprotozoal and cytotoxicity evaluation of sulfonamide and urea analogues of quinacrine.

Sulfonamide and urea derivatives of quinacrine with varying methylene spacer lengths were synthesised and tested for inhibition of trypanothione reductase (TryR) and for activity in vitro against strains of the parasitic protozoa Trypanosoma, Leishmania, and Plasmodium. These derivatives are superior inhibitors of TryR relative to quinacrine with the best compound being 40 times more potent. Urea derivatives generally displayed good in vitro activity against all parasites.