The cerebellar (para)flocculus:A review on its auditory function and a possible role in tinnitus

The cerebellum is historically considered to be involved in motor control and motor learning. However, it is also a site of multimodal sensory and sensory-motor integration, implicated in auditory processing. The flocculus and paraflocculus are small lobes of the cerebellum, in humans located in the cerebellopontine angle. The last two decades, both structures have been a subject of interest in hearing loss and tinnitus research. The current review summarizes insights on the auditory function of the (para)flocculus and its contribution to hearing loss and tinnitus. This leads to the hypothesis of a feedback loop between the paraflocculus and the auditory cortex. Disruption of this loop may be instrumental in both maintaining tinnitus and reducing tinnitus. Although the research mostly has been performed in animals, the implications in humans are also discussed. If the (para)flocculus indeed comprises an auditory function and is part of a tinnitus-mechanism, this would potentially open up new treatment options that involve direct intervention at the (para)flocculus

Intervention for unruptured high-grade intracranial dural arteriovenous fistulas:a multicenter study

OBJECTIVE The risk-to-benefit profile of treating an unruptured high-grade dural arteriovenous fistula (dAVF) is not clearly defined. The aim of this multicenter retrospective cohort study was to compare the outcomes of different interventions with observation for unruptured high-grade dAVFs.METHODS The authors retrospectively reviewed dAVF patients from 12 institutions participating in the Consortium for Dural Arteriovenous Fistula Outcomes Research (CONDOR). Patients with unruptured high-grade (Borden type II or III) dAVFs were included and categorized into four groups (observation, embolization, surgery, and stereotactic radiosurgery [SRS]) based on the initial management. The primary outcome was defined as the modified Rankin Scale (mRS) score at final follow-up. Secondary outcomes were good outcome (mRS scores 0-2) at final follow-up, symptomatic improvement, all-cause mortality, and dAVF obliteration. The outcomes of each intervention group were compared against those of the observation group as a reference, with adjustment for differences in baseline characteristics.RESULTS The study included 415 dAVF patients, accounting for 29, 324, 43, and 19 in the observation, embolization, surgery, and SRS groups, respectively. The mean radiological and clinical follow-up durations were 21 and 25 months, respectively. Functional outcomes were similar for embolization, surgery, and SRS compared with observation. With observation as a reference, obliteration rates were higher after embolization (adjusted OR [aOR] 7.147, p = 0.010) and surgery (aOR 33.803, p &lt; 0.001) and all-cause mortality was lower after embolization (imputed, aOR 0.171, p = 0.040). Hemorrhage rates per 1000 patient-years were 101 for observation versus 9, 22, and 0 for embolization (p = 0.022), surgery (p = 0.245), and SRS (p = 0.077), respectively. Nonhemorrhagic neurological deficit rates were similar between each intervention group versus observation.CONCLUSIONS Embolization and surgery for unruptured high-grade dAVFs afforded a greater likelihood of obliteration than did observation. Embolization also reduced the risk of death and dAVF-associated hemorrhage compared with conservative management over a modest follow-up period. These findings support embolization as the first-line treatment of choice for appropriately selected unruptured Borden type II and III dAVFs.</p

A protein–DNA docking benchmark

We present a protein–DNA docking benchmark containing 47 unbound–unbound test cases of which 13 are classified as easy, 22 as intermediate and 12 as difficult cases. The latter shows considerable structural rearrangement upon complex formation. DNA-specific modifications such as flipped out bases and base modifications are included. The benchmark covers all major groups of DNA-binding proteins according to the classification of Luscombe et al., except for the zipper-type group. The variety in test cases make this non-redundant benchmark a useful tool for comparison and development of protein–DNA docking methods. The benchmark is freely available as download from the internet

The Role of Inflammation in Tinnitus:A Systematic Review and Meta-Analysis

Subjective tinnitus is the perception of sound without the presence of an external source. Increasing evidence suggests that tinnitus is associated with inflammation. In this systematic review, the role of inflammation in subjective tinnitus was studied. Nine animal and twenty human studies reporting inflammatory markers in both humans and animals with tinnitus were included. It was established that TNF-α and IL-1β are increased in tinnitus, and that microglia and astrocytes are activated as well. Moreover, platelet activation may also play a role in tinnitus. In addition, we elaborate on mechanisms of inflammation in tinnitus, and discuss potential treatment options targeting inflammatory pathways

Information-driven protein–DNA docking using HADDOCK: it is a matter of flexibility

Intrinsic flexibility of DNA has hampered the development of efficient protein−DNA docking methods. In this study we extend HADDOCK (High Ambiguity Driven DOCKing) [C. Dominguez, R. Boelens and A. M. J. J. Bonvin (2003) J. Am. Chem. Soc. 125, 1731–1737] to explicitly deal with DNA flexibility. HADDOCK uses non-structural experimental data to drive the docking during a rigid-body energy minimization, and semi-flexible and water refinement stages. The latter allow for flexibility of all DNA nucleotides and the residues of the protein at the predicted interface. We evaluated our approach on the monomeric repressor−DNA complexes formed by bacteriophage 434 Cro, the Escherichia coli Lac headpiece and bacteriophage P22 Arc. Starting from unbound proteins and canonical B-DNA we correctly predict the correct spatial disposition of the complexes and the specific conformation of the DNA in the published complexes. This information is subsequently used to generate a library of pre-bent and twisted DNA structures that served as input for a second docking round. The resulting top ranking solutions exhibit high similarity to the published complexes in terms of root mean square deviations, intermolecular contacts and DNA conformation. Our two-stage docking method is thus able to successfully predict protein−DNA complexes from unbound constituents using non-structural experimental data to drive the docking

Характеристика механизма функционирования форм хозяйствования с иностранными инвестициями

Механизм функционирования предприятия с иностранными инвестициями неразрывно связан с понятиями "хозяйственный механизм" и "механизм функционирования предприятия". В экономической науке советского периода широко применялся термин "хозяйственный механизм". Рассматривался хозяйственный механизм отдельного предприятия, отрасли, экономики страны в целом, то есть рассматривался хозяйственный механизм экономических систем различного уровня

Corporate Governance and the Value of Excess Cash Holdings of Large European Firms

We examine the relation between the quality of corporate governance and the value of excess cash for large European firms (FTSEurofirst 300 Index). We use Deminor ratings for Shareholder rights, Takeover defences, Disclosure and Board as proxies for the quality of corporate governance. We find that the value of excess cash is positively related to the Takeover defences score only. It seems that governance mechanisms—except the market for corporate control—are not strong enough to prevent managers from wasting excess cash. For non-UK firms we find that the value of €1 of excess cash in a poorly governed firm is valued at only €0.89 while the value is €1.45 for a good governed firm. We show that poorly governed firms dissipate excess cash relatively quickly with a negative impact on their operating performance as a result

Cerebellar Gray Matter Volume in Tinnitus

Tinnitus is the perception of sound without an external source. The flocculus (FL) and paraflocculus (PFL), which are small lobules of the cerebellum, have recently been implicated in its pathophysiology. In a previous study, the volume of the (P)FL-complex correlated with tinnitus severity in patients that had undergone cerebellopontine angle (CPA) tumor removal. In this study, the relation between tinnitus and gray matter volume (GMV) of the (P)FL-complex, GMV of the other cerebellar lobules and GMV of the cerebellar nuclei is investigated in otherwise healthy participants. Data was processed using the SUIT toolbox, which is dedicated to analysis of imaging data of the human cerebellum. GMV of all cerebellar lobules and nuclei were similar between tinnitus and non-tinnitus participants. Moreover, no relation was present between tinnitus severity, as measured by the Tinnitus Handicap Inventory, and (P)FL-complex GMV, tonsil GMV, or total cerebellar cortical GMV. These results suggest that in otherwise healthy participants, in contrast to participants after CPA tumor removal, no relation between the GMV of neither the (P)FL-complex nor other cerebellar lobules and tinnitus presence and severity exists. These findings indicate that a relation only exists when the (P)FL-complex is damaged, for instance by a CPA tumor. Alternatively, it is possible that differences in (P)FL-complex GMVs are too small to detect with a voxel-based morphometry study. Therefore, the role of the (P)FL-complex in tinnitus remains to be further studied

Electrical modulation of the sympathetic nervous system in order to augment cerebral blood flow: a protocol for an experimental study

Introduction: Cerebral blood flow (CBF) is regulated by several mechanisms. Neurogenic control has been a matter of debate, even though several publications reported the effects of changes in sympathetic tone on CBF. Transcutaneous electrical nerve stimulation and spinal-cord stimulation have been shown to influence peripheral and cerebral blood flow through a sympathetic pathway. The authors hypothesise that certain pathological conditions result in a relative increase in the neurogenic regulation of CBF and that this regulation can be modulated electrically. Methods and analysis: Patients with cerebral vasospasm after subarachnoid haemorrhage will be included. The experimental set-up measures several parameters that are involved in cerebral blood flow regulation in patients with cerebral vasospasm after subarachnoid haemorrhage. Measurements are taken at baseline and with stimulation in several frequencies. An ad hoc statistical analysis is used to evaluate different settings of the electrical stimulation. Autoregulation is evaluated with transfer function analysis and autoregulatory index calculations. Ethics and dissemination: Ethical registration was granted by Medical Review Ethics Committee Groningen (ID METc 2010.123). All participants provide written informed consent on participation. Upon finishing a pilot study to investigate feasibility and effect, either future prospective (randomised) studies will be designed, or other modalities of electrical stimulation will be explored using the same set-up

Long-Term Patient-Reported Outcome of Radiofrequency Thalamotomy for Tremor

Background: Thalamotomy is an endorsed treatment for medication-refractory tremor. It used to be the standard, but nowadays deep brain stimulation (DBS) has become the treatment option of choice. Nevertheless, DBS has the disadvantage of hardware failure, battery replacement, and frequent setting adjustment. Radiofrequency (RF) thalamotomy lacks these issues, is relatively inexpensive, and has a broad applicability in patients with significant comorbidity. Therefore, we analyzed the long-term patient-reported outcome of RF thalamotomy in a cohort of patients with an otherwise intractable tremor. Methods: A single-center cohort of 27 consecutive patients with intractable tremor was assessed after unilateral RF thalamotomy. Over time, 4 patients had died because of non-related causes. In total, 21 patients responded to a telephone survey to assess their personal judgment on postoperative tremor severity, using a validated tremor scale, adverse events, recurrence, and patient satisfaction. The median time between surgery and telephone survey was 39 months (range 12-126). Seven patients had an additional analysis with postoperative imaging, video-assisted electromyography tremor registration, and a self-reported treatment effect (SRTE) assessment. Results: Nineteen out of 21 patients (90.5%) reported absence or significant improvement of their tremor. The rating score (WHIGET/UPDRS-III) dropped significantly from a mean of 3.57 preoperatively to 1.05 postoperatively (p < 0.001). Eleven patients (52.4%) reported adverse events, but the majority (76.2%) did not consider the adverse events to be severe. SRTE assessment showed a direct postoperative effect of 89.6 of 100 points (SD 10.8), with a gradual decrease to 75.3 (SD 23.5) during follow-up. Conclusions: RF thalamotomy is a very effective long-term treatment for medication-refractory tremor and should therefore be considered in patients with a refractory unilateral tremor