High Levels Of Stimulation Research Articles

Abstract A11: Insulin-like growth factor vaccine for the global prevention of adult cancers

Abstract The purpose of this study is to develop a single vaccine that will prevent a variety of different cancers. It functions by reducing the supply of insulin-like growth factor (IGF) required for carcinogenesis. A safe, widely applicable preemptive treatment can greatly curtail cancer deaths. Primary prevention precludes the confounding problems associated with advanced cancer such as its resistance to treatment, its eventual recurrence and the progression to metastatic disease. This novel prevention strategy is based on studies of a small population of individuals in Ecuador who are cancer free their entire lifetime due to genetically low IGF levels. In contrast, 14% of their IGF-replete relatives succumbed to 20 different types of malignancy. That compelling human example of the benefit of reduced IGF activity suggests that the initiation or early progression of many cancers requires IGF. Thus, the objective is to develop protective vaccines to neutralize the multiple activities of IGF that promote oncogenesis. The ultimate goal is to vaccinate at risk adults and achieve the same protection from cancer experienced by the IGF-deficient Ecuadorians. The concept is predicated on the hypothesis that a lingering high level of IGF stimulation is superfluous after adolescence and, in later years, becomes detrimental to health. There are strong survival benefits for its simultaneous mitogenic, hypertrophic and antiapoptotic activities to operate during growth and development. Alas, there is no evolutionary pressure to develop a post-reproductive IGF shutoff mechanism. So, as science and medicine steadily extend the human lifespan, we find ourselves in the dilemma of having to accommodate a persistent pro-cancer hormone with little or no other purpose. This hypothesis fits with the age dependent increase of cancer incidence. Conventional and cutting-edge, nanofiber-based epitope vaccines have been produced to test this idea. They are designed to actively induce antibodies that either neutralize IGF directly or block a key enzyme that regulates IGF bioavailability. The continuous presence of such inhibitory antibodies would keep IGF activity at a constantly low level and thereby preemptively block the development of incipient cancers later in life. Antisera from mice immunized with those vaccines contained epitope-specific IgG antibodies that were reactive with recombinant IGF in ELISA studies. An ultrafiltration method was also used to demonstrate specific binding of recombinant 125I-IGF after incubation with undiluted antiserum versus non-immune control sera (conditions that mimic in vivo therapy). Exploratory tests indicated that the vaccine delayed the appearance of tumors in mice that develop sarcomas due to SV40 Tag expression. Safety is undeniably paramount for any new cancer prevention therapy and apprehension about targeting the ubiquitously expressed IGF is understandable. In terms of human health consequences however, the IGF-deficient Ecuadorians represent a worst-case scenario since they are severely depleted from birth onwards. Although very short due to their life-long IGF deficit, this cancer-free population is surprisingly healthy and long-lived (some >80 years old). Nevertheless, to further ensure safety the IGF-suppressive vaccines will be administered exclusively to fully grown and developed adults. Preemptive vaccination at 40-50 years old would be most effective since a majority of human malignancies occur beyond the age of 60 and because this postponement will circumvent impairment of normal growth or other juvenile functions. The prevention vaccines could be used; 1) for people with a genetic likelihood to develop familial cancer, 2) as an adjuvant following precancerous growth removal, 3) to inhibit relapse for patients in remission, and 4) as a general prophylactic to curtail sporadic, age-dependent cancers. Citation Format: Victor Raso. Insulin-like growth factor vaccine for the global prevention of adult cancers. [abstract]. In: Proceedings of the Twelfth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2013 Oct 27-30; National Harbor, MD. Philadelphia (PA): AACR; Can Prev Res 2013;6(11 Suppl): Abstract nr A11.

Ipsi- and contralateral interaction in the 40 Hz auditory steady state responses (ASSRs) with two carriers at 60 dB SPL

Objective: Auditory steady state responses have been suggested for simultaneous threshold assessment using the multiple ASSR (MASSR) technique. However, at least at high stimulation levels, strong interactions reduce response amplitudes. The present study investigates ASSR interaction at a moderate stimulus level. Design: Sinusoidal carriers modulated at rates near 40 Hz were used as probe. Unmodulated and modulated interferers were presented ipsi- or contralaterally. Study sample: Twenty normal-hearing subjects participated. Results: Unmodulated interferers did not significantly change ASSR amplitudes. Modulated interferers, presented ipsilaterally or contralaterally, both significantly reduced the ASSR SNR by 13% and 8%, respectively. Conclusions: To compensate for the average SNR reduction would require a 32% and 18% longer measurement time for ipsi- and contralateral interferers, respectively, far less than the doubling of measurement time for two single measurements, emphasizing the MASSR technique advantage. However, the largest reduction for a single subject was 22% for the amplitude and 28% for the SNR, almost completely undoing the benefit in measurement time in MASSR. The individually varying interaction effects even at 60 dB SPL clearly limits the advantage of using the MASSR for modulation rates near 40 Hz over corresponding single ASSR measurements, at least for two simultaneous carriers.

7. Cortical plasticity in patients with l-dopa induced dyskinesias

Objective: Effects of PAS 25 protocol in PD patients with l -dopa induced dyskinesias (LID). Subjects and methods: We analyzed 10 patients with PD who had dyskinesias as a side effect of l -dopa therapy and 10 healthy subjects in control group (CG). Plasticity and excitability of the hand primary motor cortex of the more affected side were evaluated using transcranial magnetic stimulation (TMS) techniques. Recording was done before (Tb), immediately (T0) and 30 min after procedure (T30). Patients were tested in “off” and “on” states. Results: There was no difference for MEP between groups. Patients with l -dopa induced dyskinesias with medication immediately after PAS, showed decrease of slope at higher levels of stimulation (150% rMT, p = 0.058) compared with CG. All subjects show a decrease of SP ( p p = 0.034) compared with CG, without significance for ICF ( p = 0.578), regardless of the applied procedures. Conclusion: Patients with LID have a higher inhibition, probably due to involuntary movements. It is possible that their brain is “working” at smaller scale. PAS 25 protocols had no significant effect on cortical plasticity in patients with PD who have LID.

To TUI or not to TUI: Evaluating performance and preference in tangible vs. graphical user interfaces

Tangible user interfaces (TUIs) are often compared to graphical user interfaces (GUIs). However, the existing literature is unable to demonstrate clear advantages for either interface, as empirical studies yielded different findings, sometimes even contradicting ones. The current study set out to conduct an in-depth analysis of the strengths and weaknesses of both interfaces, based on a comparison between similar TUI and GUI versions of a modeling and simulation system called “FlowBlocks”. Results showed most users preferred the TUI version over the GUI version. This is a surprising finding, considering both versions were equivalent in regard to most performance parameters, and the TUI version was even perceived as inferior to the GUI version in regard to usability. Interviews with users revealed this preference stemmed from high levels of stimulation and enjoyment, derived from three TUI properties: physical interaction, rich feedback, and high levels of realism. Potential underlying mechanisms for these findings and practical implications are discussed.

Relationship of plasma neuropeptide Y with angiographic, electrocardiographic and coronary physiology indices of reperfusion during ST elevation myocardial infarction

ObjectivesThe co-transmitter neuropeptide Y (NPY) is released during high levels of sympathetic stimulation and is a potent vasoconstrictor. We defined the release profile of plasma NPY during acute ST elevation...

A translational platform for prototyping closed-loop neuromodulation systems

While modulating neural activity through stimulation is an effective treatment for neurological diseases such as Parkinson's disease and essential tremor, an opportunity for improving neuromodulation therapy remains in automatically adjusting therapy to continuously optimize patient outcomes. Practical issues associated with achieving this include the paucity of human data related to disease states, poorly validated estimators of patient state, and unknown dynamic mappings of optimal stimulation parameters based on estimated states. To overcome these challenges, we present an investigational platform including: an implanted sensing and stimulation device to collect data and run automated closed-loop algorithms; an external tool to prototype classifier and control-policy algorithms; and real-time telemetry to update the implanted device firmware and monitor its state. The prototyping system was demonstrated in a chronic large animal model studying hippocampal dynamics. We used the platform to find biomarkers of the observed states and transfer functions of different stimulation amplitudes. Data showed that moderate levels of stimulation suppress hippocampal beta activity, while high levels of stimulation produce seizure-like after-discharge activity. The biomarker and transfer function observations were mapped into classifier and control-policy algorithms, which were downloaded to the implanted device to continuously titrate stimulation amplitude for the desired network effect. The platform is designed to be a flexible prototyping tool and could be used to develop improved mechanistic models and automated closed-loop systems for a variety of neurological disorders.

Phosphatidylethanolamines Glycation, Oxidation, and Glycoxidation: Effects on Monocyte and Dendritic Cell Stimulation

Lipid glycation is a non-enzymatic reaction between glucose and the free amino group of aminophospholipids, particularly in chronic hyperglycemia. Glycated phosphatidylethanolamine have been found in plasma and atherosclerotic plaques of diabetic patients and was correlated with increased oxidative and inflammatory stress in diabetes. However, the biological roles of glycated lipids are not fully understood. In this study, we evaluated the effect of palmitoyl-oleoyl-phosphatidylethanolamine (POPE) oxidation, glycation, and glycoxidation products on monocyte and myeloid dendritic cell stimulation. Flow cytometry analysis was used to evaluate the capability of each modified PE to induce the expression of different cytokines (IL-1β, IL-6, IL-8, MIP-1β, and TNF-α) in monocytes or myeloid dendritic cells (mDC). Our results showed that PE modifications induced different effect on the stimulation of cells producing cytokines. All PE modifications induced higher frequencies of cytokine-producing cells than basal state. Higher stimulation levels were obtained with glycated POPE, followed by glycoxidized POPE. In contrast, oxidized POPE negatively regulated the frequency of monocytes and mDC producing cytokines, when compared with non-modified POPE. In conclusion, we verified that PE glycation, compared with oxidation and glycation plus oxidation, had higher ability to stimulate monocytes and mDC. Thus detection of increased levels of PE glycation in diabetes could be considered a predictor of a inflammatory state.

CaMKII points the way

![Figure][1] Over time, CaMKII (green) accumulates in a dendrite’s spine (arrow) and adjacent regions of the shaft (bracket). Synapses that receive high levels of stimulation typically grow stronger. [Lemieux et al.][2] show that a protein complex that lands on microtubules near these

A New view of Insulin Action

Insulin not only stimulates the Na-K-pump,but by stimulating the Na:H exchange pump increases intracellular pH, pHi. Fidelman et al (1982) found, as predicted by thermodynamic theory, the effect of insulin on glycolysis varied linearly with log[Na]o with the insulin effect being converted from stimulation of glycolysis to a 51% inhibition at 0.12 mM Nao.Zierler & Rabinowitz (1964) demonstrated in the forearm of human males that levels of insulin too low to affect glucose uptake, as little as 38 micro units per ml, was sufficient to stimulate the Na-K-pump, as reflected by increased potassium uptake, while producing no effect upon glucose uptake. This one experiment forces us to realize that the main action of insulin is not to regulate blood glucose levels, but to regulate the Na-K-pump and Na:H exchange. Since the Na-K-pump uses about 25% of the ATP production in a resting muscle, stimulation of the Na-K-pump increases the consumption of ATP so much that at high levels of stimulation, it is necessary to get more glucose into the cell to manufacture more ATP.Since insulin decreases Nai, elevates pHi, and increases production of ATP, one would expedt that the decreased insulin, such as seen in diabetes or in fasting would result in the reverse of these changes. Lowering plasma levels of insulin in rats by small doses of streptozotocin or by fasting produced an increase in Nai of about 30%, a decrease in pHi of 0.15 units, and a 24% decrease in ATPi.The action of thiazide diuretics to cause type 2 diuretics has been shown to be due to their ability to cause potassium loss. Not surprisingly, diets with large amounts of potassium and small amounts of sodium have been shown to reverse diabetes.

Activation of muscarinic receptors inhibits neurogenic nitric oxide in the corpus cavernosum

The functional role of cholinergic transmission in erection is still far from being fully elucidated. This work aims to further elucidate the modulatory role of neostigmine on NO in the corpus cavernosum and to highlight whether cholinergic transmission in the penis modulates sildenafil action. The isolated rabbit corpus cavernosum and measurement of intracavernosal pressure in the anesthetized rat model were used. Neostigmine (0.02mg/kg) reduced increase of intracavernosal pressure/mean arterial pressure (ICP/MAP) next to cavernous nerve stimulation. Higher doses (0.06 and 0.4mg/kg) potentiated ICP/MAP rise and atropine (1.5 and 10mg/kg) did the opposite. In vitro, neostigmine (10−5 and 10−4M) potentiated neurogenic relaxations and this effect was significantly inhibited by hexamethonium (10−4M) or Nω-propyl-l-arginine (3×10−5M) and partially but significantly reduced in the presence of atropine. Lower dose neostigmine (10−7M), inhibited electrically induced relaxation over the range of 1–4Hz, atropine (10−6M) almost abolished this inhibitory effect as well as NG-nitro-l-arginine (10−5M). It was also significantly reduced by selective nNOS inhibitor Nω-propyl-l-arginine (3×10−5M). Nicotine (10−4M) significantly potentiated electrically induced relaxations amounting to 84.625±8.06% at 1Hz and potentiated the effect of sildenafil synergistically. Hexamthonium did the opposite. The potentiatory effect of sildenafil on neurogenic erection was significantly reduced by low dose neostigmine both in vitro and in vivo. This study provides evidence that muscarinic receptors may modulate NO synthesis in nitrergic nerves by inhibiting nNOS and high level of cholinergic stimulation may activate nicotinic receptors to promote erection probably by potentiating NO synthesis in nitrergic nerves.

Interactive gaming reduces experimental pain with or without a head mounted display

While virtual reality environments have been shown to reduce pain, the precise mechanism that produces the pain attenuating effect has not been established. It has been suggested that it may be the ability to command attentional resources with the use of head mounted displays (HMDs) or the interactivity of the environment. Two experiments compared participants’ pain ratings to high and low levels of electrical stimulation while engaging in interactive gaming with an HMD. In the first, gaming with the HMD was compared to a positive emotion induction condition; and in the second experiment the HMD was compared to a condition in which the game was projected onto a wall. Interactive gaming significantly reduced numerical ratings of painful stimuli when compared to the baseline and affect condition. However, when the two gaming conditions were directly compared, they equally reduced participants’ pain ratings. These data are consistent with past research showing that interactive gaming can attenuate experimentally induced pain and its effects are comparable whether presented in a head mounted display or projected on a wall.

Rapid task acquisition of spatial-delayed alternation in an automated T-maze by mice

The spatial-delayed alternation task using a T-maze is the standard method for testing working memory in rodents and is widely used. Until now, however, there has been a gap in the understanding of the underlying brain mechanisms. The development of new manganese-enhanced brain imaging methods now permit a more specific examination of these mechanisms by allowing behavioural brain stimulation to take place outside the MRI scanner and the scan identifying the activation of specific brain regions to take place subsequently. The requirements for this method are a frequent repetition of the behaviour of interest, a control group that differs in only one task parameter and the minimization of unspecific environmental factors to avoid irrelevant stimulation. To meet these requirements, a fully automated spatial-delayed alternation task in a T-maze was developed that used identity detectors and automated gates to route mice individually from their social home cage to the T-maze. An experimental and a control group of mice were trained in procedures that differed only in the parameter “working-memory based alternation”. Our data demonstrate that both groups can be trained concurrently with a rapid procedure using the automated T-maze. With its high level of stimulation, the minimization of unspecific stimulation through environmental factors and the simultaneous training of a control group that differs in only one task parameter our set-up and procedure met the requirements of new imaging techniques for the study of the influence of a specific cognitive component of spatial-delayed alternation on activity in specific brain regions.

Protective effect against oxygen reactive species and skin fibroblast stimulation of Couroupita guianensis leaf extracts

In this study, hydroalcoholic leaf extracts of Couroupita guianensis were examined for antioxidant activity, phytochemical and total phenolic composition, stimulation of human skin fibroblast (HSF) proliferation and UV-absorption. The radical scavenging capacity, reducing power and protection against joint oxidation of linoleic acid and β-carotene bleaching oxidation in emulsion were used to evaluate the antioxidant activity. The results of this study strongly indicate in vitro antioxidant activity, which may be due to the presence of a high total phenolic content. In order to identify active principles, the extracts were submitted to fractionation and the compounds isolated were the flavonoids 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (1), 7-hydroxy-5-methoxy-6,8-dimethylflavanone (2) and the phenolic acid 4-hydroxybenzoic acid (3). In addition, a high level of stimulation of HSF proliferation and significant absorption of UV radiation were also observed. The results suggest that the hydroalcoholic leaf extracts of C. guianensis have promising skin care properties.

Electrical stimulation of the sural cutaneous afferent nerve controls the amplitude and onset of the swing phase of locomotion in the spinal cat

Sensory feedback plays a crucial role in the control of locomotion and in the recovery of function after spinal cord injury. Investigations in reduced preparations have shown that the locomotor cycle can be modified through the activation of afferent feedback at various phases of the gait cycle. We investigated the effect of phase-dependent electrical stimulation of a cutaneous afferent nerve on the locomotor pattern of trained spinal cord-injured cats. Animals were first implanted with chronic nerve cuffs on the sural and sciatic nerves and electromyographic electrodes in different hindlimb muscles. Cats were then transected at T12 and trained daily to locomote on a treadmill. We found that electrical stimulation of the sural nerve can enhance the ongoing flexion phase, producing higher (+129%) and longer (+17.4%) swing phases of gait even at very low threshold of stimulation. Sural nerve stimulation can also terminate an ongoing extension and initiate a flexion phase. A higher prevalence of early switching to the flexion phase was observed at higher stimulation levels and if stimulation was applied in the late stance phase. All flexor muscles were activated by the stimulation. These results suggest that electrical stimulation of the sural nerve may be used to increase the magnitude of the swing phase and control the timing of its onset after spinal cord injury and locomotor training.

Activation of group I metabotropic glutamate receptors modulates locomotor-related motoneuron output in mice

Fast glutamatergic transmission via ionotropic receptors is critical for the generation of locomotion by spinal motor networks. In addition, glutamate can act via metabotropic glutamate receptors (mGluRs) to modulate the timing of ongoing locomotor activity. In the present study, we investigated whether mGluRs also modulate the intensity of motor output generated by spinal motor networks. Application of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) reduced the amplitude and increased the frequency of locomotor-related motoneuron output recorded from the lumbar ventral roots of isolated mouse spinal cord preparations. Whole cell patch-clamp recordings of spinal motoneurons revealed multiple mechanisms by which group I mGluRs modulate motoneuron output. Although DHPG depolarized the resting membrane potential and reduced the voltage threshold for action potential generation, the activation of group I mGluRs had a net inhibitory effect on motoneuron output that appeared to reflect the modulation of fast, inactivating Na(+) currents and action potential parameters. In addition, group I mGluR activation decreased the amplitude of locomotor-related excitatory input to motoneurons. Analyses of miniature excitatory postsynaptic currents indicated that mGluRs modulate synaptic drive to motoneurons via both pre- and postsynaptic mechanisms. These data highlight group I mGluRs as a potentially important source of neuromodulation within the spinal cord that, in addition to modulating components of the central pattern generator for locomotion, can modulate the intensity of motoneuron output during motor behavior. Given that group I mGluR activation reduces motoneuron excitability, mGluRs may provide negative feedback control of motoneuron output, particularly during high levels of glutamatergic stimulation.

Alterations in Mitochondrial State 4→3 Transition Underlie Stress-Induced Energetic-Redox Imbalance and Myocyte Dysfunction in Diabetic Mice

Diabetes is a syndrome in which mitochondrial alterations may participate in the dysfunction, and ultimately failure of several organs. The diabetic heart in particular can be subjected to both glycemic level oscillations and increased workload (via β-stimulation), events that may further deteriorate its mechanical properties. Here we show that when diabetic heart (db/db) cells are challenged with high levels of extracellular glucose (30 mM) and concomitant β-adrenergic stimulation via isoproterenol (ISO), intracellular GSH is greatly diminished while superoxide and H2O2 generation substantially increased. The typical enhancement in sarcomere shortening and whole Ca2+ transient driven by β-adrenergic stimulation is blunted in db/db cells, along with hampered relaxation and Ca2 reuptake. Mitochondria isolated from db/db hearts subjected to high-glucose/ISO regimen exhibit markedly decreased coupling ratios from respiratory complexes I, II, and IV while ROS emission is greatly increased, under both forward and reverse electron transport. These changes reflect a profound alteration in the crucial (energy supplying) state 4→3 transition that ultimately results in lowered ATP synthesis and in a “non-stop” reactive oxygen species (ROS) emission in the presence of ADP. Incubating high-glucose/ISO treated db/db myocytes with cell-permeable GSH restores intracellular GSH, blunts ROS production and fully rescues contractility/relaxation in these myocytes. These results show the direct role played by an oxidized redox environment in triggering the negative synergy among mitochondrial ROS and energetics leading to the E-C coupling impairment. Our study maps mitochondrial sites, i.e. state 4→3 transition, that in diabetic heart cells account, at least in part, for excess ROS emission and loss in energy supply when metabolically and energetically challenged.

Pair-bonding and parental care in cricetid rodents: a comparative study

The cricetid rodents (hamsters, voles, and gerbils) show substantial inter-specific variation in their social organization, mating strategies, and patterns of social behavior, including parental care. In the present study, behaviors related to pair-bonding and parental activities were evaluated in male–female pairs of six cricetid species (Cricetulus migratorius Pallas, 1773, Clethrionomys rutilus Pallas, 1779, Microtus arvalis Pallas, 1778, Microtus socialis Pallas, 1773, Lasiopodomys brandti Radde, 1852, and Meriones unguiculatus Milne-Edwards, 1867) observed under laboratory conditions. These species were chosen due to particular differences in their mating strategies and the spatial-and-ethological population structure (Types I–IV). The results of the study show that there is a pronounced tendency towards both reinforcement of pair-bonds and increasing rate of direct parental care, especially paternal one, when solitary or gregarious species (Types I and II—C. migratorius and C. rutilus) are compared with the ones living in family groups (Type III—M. arvalis and M. socialis and Type IV—L. brandti and M. unguiculatus). Parental investment of males is mainly related to additional tactile stimulation of infants. A high level of tactile stimulation of pups promotes an increase in subsequent paternal care and reinforcement of pair-bonding, and, conversely, a deficit of tactile stimulation negatively affects the development of paternal behavior and social relationships. Thus, tactile stimulation can be regarded as one of the proximate mechanisms of socialization that plays an essential role in the evolution of sociality, i.e., transition to a family-group mode of life in rodents.

A direct approach for the design of chirp stimuli used for the recording of auditory brainstem responses

A recent study evaluates auditory brainstem responses (ABRs) evoked by chirps of different durations (sweeping rates) [Elberling et al. (2010). J. Acoust. Soc. Am. 128, 215-223]. The study demonstrates that shorter chirps are most efficient at higher levels of stimulation whereas longer chirps are most efficient at lower levels. Mechanisms other than the traveling wave delay, in particular, upward spread of excitation and changes in cochlear-neural delay with level, are suggested to be responsible for these findings. As a consequence, delay models based on estimates of the traveling wave delay are insufficient for the design of chirp stimuli, and another delay model based on a direct approach is therefore proposed. The direct approach uses ABR-latencies from normal-hearing subjects in response to octave-band chirps over a wide range of levels. The octave-band chirps are constructed by decomposing a broad-band chirp, and constitute a subset of the chirp. The delay compensations of the proposed model are similar to those found in the previous experimental study, which thus verifies the results of the proposed model.

Functional Roles of the N- and C-Terminal Regions of the Human Mitochondrial Single-Stranded DNA-Binding Protein

Biochemical studies of the mitochondrial DNA (mtDNA) replisome demonstrate that the mtDNA polymerase and the mtDNA helicase are stimulated by the mitochondrial single-stranded DNA-binding protein (mtSSB). Unlike Escherichia coli SSB, bacteriophage T7 gp2.5 and bacteriophage T4 gp32, mtSSBs lack a long, negatively charged C-terminal tail. Furthermore, additional residues at the N-terminus (notwithstanding the mitochondrial presequence) are present in the sequence of species across the animal kingdom. We sought to analyze the functional importance of the N- and C-terminal regions of the human mtSSB in the context of mtDNA replication. We produced the mature wild-type human mtSSB and three terminal deletion variants, and examined their physical and biochemical properties. We demonstrate that the recombinant proteins adopt a tetrameric form, and bind single-stranded DNA with similar affinities. They also stimulate similarly the DNA unwinding activity of the human mtDNA helicase (up to 8-fold). Notably, we find that unlike the high level of stimulation that we observed previously in the Drosophila system, stimulation of DNA synthesis catalyzed by human mtDNA polymerase is only moderate, and occurs over a narrow range of salt concentrations. Interestingly, each of the deletion variants of human mtSSB stimulates DNA synthesis at a higher level than the wild-type protein, indicating that the termini modulate negatively functional interactions with the mitochondrial replicase. We discuss our findings in the context of species-specific components of the mtDNA replisome, and in comparison with various prokaryotic DNA replication machineries.

Auditory brainstem and cortical potentials following bone-anchored hearing aid stimulation

Patients suffering from conductive or mixed hearing loss and Single-Sided Deafness may benefit from implantable hearing devices relying on bone conducted auditory stimulation. However, with only passively cooperative patients, objective methods are needed to estimate the aided and unaided pure-tone audiogram.This study focuses on the feasibility aspect of an electrophysiological determination of the hearing thresholds with bone-anchored hearing aid stimulation. Therefore, 10 normal-hearing subjects were provided with a Baha Intenso (Cochlear Ltd.) which was temporarily connected to the Baha Softband (Cochlear Ltd.). Auditory evoked potentials were measured by auditory stimulation paradigm used in clinical routine. The amplitudes, latencies, and thresholds of the resulting auditory brainstem responses (ABR) and the cortically evoked responses (CAEP) were correlated with the respective responses without the use of the Baha Intenso.The recording of ABR and CAEP by delivering the stimuli to the Baha results in response waveforms which are comparable to those evoked by earphone stimulation and appears appropriate to be measured using the Baha Intenso as stimulator. At the ABR recordings a stimulus artifact at higher stimulation levels and a constant latency shift caused by the Baha Intenso has to be considered. The CAEP recording appeared promising as a frequency specific objective method to approve the fitting of bone-anchored hearing aids.At all measurements, the ABR and CAEP thresholds seem to be consistent with the normal hearing of the investigated participants. Thus, a recording of auditory evoked potentials using a Baha is in general possible if specific limitations are considered.