Neuroauditory Toxicity of Artemisinin Combination Therapies—Have Safety Concerns Been Addressed?

Although artemisinin-based combination therapies (ACTs) are widely viewed as safe drugs with a wide therapeutic dose range, concerns about neuroauditory safety of artemisinins arose during their development. A decade ago, reviews of human data suggested a potential neuro-ototoxic effect, but the validity of these findings was questioned. With 5–10 years of programmatic use, emerging artemisinin-tolerant falciparum malaria in southeast Asia, and the first calls to consider an increased dose of artemisinins, we review neuroauditory safety data on ACTs to treat uncomplicated falciparum malaria. Fifteen studies reported a neurological or auditory assessment. The large heterogeneity of neuro-ototoxic end points and assessment methodologies and the descriptive nature of assessments hampered a formal meta-analysis and definitive conclusions, but they highlight the persistent lack of data from young children. This subgroup is potentially most vulnerable to any neuroauditory toxicity because of their development stage, increased malaria susceptibility, and repeated ACT exposure in settings lacking robust safety monitoring

Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria

<p>Abstract</p> <p>Background</p> <p>Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the <it>stria vascularis</it>, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment.</p> <p>Methods</p> <p>The temporal bones of seven mice with cerebral malaria-four with hearing impairment, three without hearing impairment-were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier.</p> <p>Results</p> <p>Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals.</p> <p>Conclusion</p> <p>Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.</p

The effects of mild hypothermia on the electrode insertion trauma in a murine whole organ cochlea culture

IntroductionLocal therapeutic hypothermia (32°C) has been linked experimentally to an otoprotective effect in the electrode insertion trauma. The pathomechanism of the electrode insertion trauma is connected to the activation of apoptosis and necrosis pathways, pro-inflammatory and fibrotic mechanisms. In a whole organ cochlea culture setting the effect of therapeutic hypothermia in an electrode insertion trauma model is evaluated.Material and MethodsThe cochleae of C57Bl6/J mice (Charles River®, Freiburg, Germany) are cultured for 24 hours at 37°C and 32°C after inserting a fishing line through the round window simulating an insertion trauma. The resulting effect was evaluated for the apoptotic reaction – B-cell-Lymphoma-2-Associated-X-Protein (BAX), B-Cell-Lymphoma-2-Protein (BCL2) and Cleaved-Caspase-3 (CC3) –, the inflammatory response – Tumor-Necrosis-Factor-Alpha (TNFα), Interleukin-1-Beta (IL-1Imm) and Cyclooxygenase-2 (COX2) – and proliferation process – Transforming-Growth-Factor-Beta-1 (TGFβ1) – using immunohistochemistry and real-time PCR technique. A minimum of 12 cochlea per experiment were used.ResultsA pro-apoptotic situation was observed in the normothermic group (BAX, CC3 ˃ Bcl2) whereas an anti-apoptotic constellation was found at 32°C culture conditions (BAX, CC3 &lt; Bcl2). Furthermore the effect of the IT knowing to effect the pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression has been reproduced. This reaction was reversed with the application of therapeutic hypothermia resulting in significant lower pro-inflammatory cytokine (TNFα, Il1β) and enzyme (COX2) expression. TGFβ1 was increased by hypothermia.DiscussionConcluding a protective effect of hypothermia on the experimental electrode insertion trauma can be described by an anti-apoptotic and anti-inflammatory reaction

Severe malaria in children leads to a significant impairment of transitory otoacoustic emissions--a prospective multicenter cohort study.

BACKGROUND: Severe malaria may influence inner ear function, although this possibility has not been examined prospectively. In a retrospective analysis, hearing impairment was found in 9 of 23 patients with cerebral malaria. An objective method to quickly evaluate the function of the inner ear are the otoacoustic emissions. Negative transient otoacoustic emissions are associated with a threshold shift of 20 dB and above. METHODS: This prospective multicenter study analyses otoacoustic emissions in patients with severe malaria up to the age of 10 years. In three study sites (Ghana, Gabon, Kenya) 144 patients with severe malaria and 108 control children were included. All malaria patients were treated with parental artesunate. RESULTS: In the control group, 92.6 % (n = 108, 95 % confidence interval 86.19-6.2 %) passed otoacoustic emission screening. In malaria patients, 58.5 % (n = 94, malaria vs controls p < 0.001, 95 % confidence interval 48.4-67.9 %) passed otoacoustic emission screening at the baseline measurement. The value increased to 65.2 % (n = 66, p < 0.001, 95 % confidence interval 53.1-75.5 %) at follow up 14-28 days after diagnosis of malaria. The study population was divided into severe non-cerebral malaria and severe malaria with neurological symptoms (cerebral malaria). Whereas otoacoustic emissions in severe malaria improved to a passing percentage of 72.9 % (n = 48, 95 % confidence interval 59-83.4 %) at follow-up, the patients with cerebral malaria showed a drop in the passing percentage to 33 % (n = 18) 3-7 days after diagnosis. This shows a significant impairment in the cerebral malaria group (p = 0.012 at days 3-7, 95 % confidence interval 16.3-56.3 %; p = 0.031 at day 14-28, 95 % confidence interval 24.5-66.3 %). CONCLUSION: The presented data show that 40 % of children have involvement of the inner ear early in severe malaria. In children, audiological screening after severe malaria infection is not currently recommended, but is worth investigating in larger studies

Murine malaria is associated with significant hearing impairment

<p>Abstract</p> <p>Background</p> <p><it>Plasmodium falciparum </it>malaria has been suspected to cause hearing loss. Developmental, cognitive and language disorders have been observed in children, surviving cerebral malaria. This prospective study aims to evaluate whether malaria influences hearing in mice.</p> <p>Methods</p> <p>Twenty mice were included in a standardized murine cerebral malaria model. Auditory evoked brainstem responses were assessed before infection and at the peak of the illness.</p> <p>Results</p> <p>A significant hearing impairment could be demonstrated in mice with malaria, especially the cerebral form. The control group did not show any alterations. No therapy was used.</p> <p>Conclusion</p> <p>This suggests that malaria itself leads to a hearing impairment in mice.</p

A novel approach to fractional calculus: utilizing fractional integrals and derivatives of the Dirac delta function

While the definition of a fractional integral may be codified by Riemann and Liouville, an agreed-upon fractional derivative has eluded discovery for many years. This is likely a result of integral definitions including numerous constants of integration in their results. An elimination of constants of integration opens the door to an operator that reconciles all known fractional derivatives and shows surprising results in areas unobserved before, including the appearance of the Riemann Zeta Function and fractional Laplace and Fourier Transforms. A new class of functions, known as Zero Functions and closely related to the Dirac Delta Function, are necessary for one to perform elementary operations of functions without using constants. The operator also allows for a generalization of the Volterra integral equation, and provides a method of solving for Riemann's "complimentary" function introduced during his research on fractional derivatives

A Cross-Sectional Study of People with Epilepsy and Neurocysticercosis in Tanzania: Clinical Characteristics and Diagnostic Approaches.

Neurocysticercosis (NCC) is a major cause of epilepsy in regions where pigs are free-ranging and hygiene is poor. Pork production is expected to increase in the next decade in sub-Saharan Africa, hence NCC will likely become more prevalent. In this study, people with epilepsy (PWE, n=212) were followed up 28.6 months after diagnosis of epilepsy. CT scans were performed, and serum and cerebrospinal fluid (CSF) of selected PWE were analysed. We compared the demographic data, clinical characteristics, and associated risk factors of PWE with and without NCC. PWE with NCC (n=35) were more likely to be older at first seizure (24.3 vs. 16.3 years, p=0.097), consumed more pork (97.1% vs. 73.6%, p=0.001), and were more often a member of the Iraqw tribe (94.3% vs. 67.8%, p=0.005) than PWE without NCC (n=177). PWE and NCC who were compliant with anti-epileptic medications had a significantly higher reduction of seizures (98.6% vs. 89.2%, p=0.046). Other characteristics such as gender, seizure frequency, compliance, past medical history, close contact with pigs, use of latrines and family history of seizures did not differ significantly between the two groups. The number of NCC lesions and active NCC lesions were significantly associated with a positive antibody result. The electroimmunotransfer blot, developed by the Centers for Disease Control and Prevention, was more sensitive than a commercial western blot, especially in PWE and cerebral calcifications. This is the first study to systematically compare the clinical characteristics of PWE due to NCC or other causes and to explore the utility of two different antibody tests for diagnosis of NCC in sub-Saharan Africa

Suitable Electrode Choice for Robotic-Assisted Cochlear Implant Surgery: A Systematic Literature Review of Manual Electrode Insertion Adverse Events

BACKGROUND AND OBJECTIVE: The cochlear implant (CI) electrode insertion process is a key step in CI surgery. One of the aims of advances in robotic-assisted CI surgery (RACIS) is to realize better cochlear structure preservation and to precisely control insertion. The aim of this literature review is to gain insight into electrode selection for RACIS by acquiring a thorough knowledge of electrode insertion and related complications from classic CI surgery involving a manual electrode insertion process. METHODS: A systematic electronic search of the literature was carried out using PubMed, Scopus, Cochrane, and Web of Science to find relevant literature on electrode tip fold over (ETFO), electrode scalar deviation (ESD), and electrode migration (EM) from both pre-shaped and straight electrode types. RESULTS: A total of 82 studies that include 8,603 ears implanted with a CI, i.e., pre-shaped (4,869) and straight electrodes (3,734), were evaluated. The rate of ETFO (25 studies, 2,335 ears), ESD (39 studies, 3,073 ears), and EM (18 studies, 3,195 ears) was determined. An incidence rate (±95% CI) of 5.38% (4.4–6.6%) of ETFO, 28.6% (26.6–30.6%) of ESD, and 0.53% (0.2–1.1%) of EM is associated with pre-shaped electrodes, whereas with straight electrodes it was 0.51% (0.1–1.3%), 11% (9.2–13.0%), and 3.2% (2.5–3.95%), respectively. The differences between the pre-shaped and straight electrode types are highly significant (p < 0.001). Laboratory experiments show evidence that robotic insertions of electrodes are less traumatic than manual insertions. The influence of round window (RW) vs. cochleostomy (Coch) was not assessed. CONCLUSION: Considering the current electrode designs available and the reported incidence of insertion complications, the use of straight electrodes in RACIS and conventional CI surgery (and manual insertion) appears to be less traumatic to intracochlear structures compared with pre-shaped electrodes. However, EM of straight electrodes should be anticipated. RACIS has the potential to reduce these complications

Epidemiology of taeniosis/cysticercosis in Europe, a systematic review : Western Europe

Background: Taenia solium and Taenia saginata are zoonotic parasites of public health importance. Data on their occurrence in humans and animals in western Europe are incomplete and fragmented. In this study, we aimed to update the current knowledge on the epidemiology of these parasites in this region. Methods: We conducted a systematic review of scientific and grey literature published from 1990 to 2015 on the epidemiology of T. saginata and T. solium in humans and animals. Additionally, data about disease occurrence were actively sought by contacting local experts in the different countries. Results: Taeniosis cases were found in twelve out of eighteen countries in western Europe. No cases were identified in Iceland, Ireland, Luxembourg, Norway, Sweden and Switzerland. For Denmark, Netherlands, Portugal, Slovenia, Spain and the UK, annual taeniosis cases were reported and the number of detected cases per year ranged between 1 and 114. Detected prevalences ranged from 0.05 to 0.27%, whereas estimated prevalences ranged from 0.02 to 0.67%. Most taeniosis cases were reported as Taenia spp. or T. saginata, although T. solium was reported in Denmark, France, Italy, Spain, Slovenia, Portugal and the UK. Human cysticercosis cases were reported in all western European countries except for Iceland, with the highest number originating from Portugal and Spain. Most human cysticercosis cases were suspected to have acquired the infection outside western Europe. Cases of T. solium in pigs were found in Austria and Portugal, but only the two cases from Portugal were confirmed with molecular methods. Germany, Spain and Slovenia reported porcine cysticercosis, but made no Taenia species distinction. Bovine cysticercosis was detected in all countries except for Iceland, with a prevalence based on meat inspection of 0.0002-7.82%. Conclusions: Detection and reporting of taeniosis in western Europe should be improved. The existence of T. solium tapeworm carriers, of suspected autochthonous cases of human cysticercosis and the lack of confirmation of porcine cysticercosis cases deserve further attention. Suspected cases of T. solium in pigs should be confirmed by molecular methods. Both taeniosis and human cysticercosis should be notifiable and surveillance in animals should be improved.Peer reviewe