How I do it: the endoscopic endonasal transclival approach for clipping of the ruptured vertebral artery aneurysm.

BACKGROUND: Vertebral artery aneurysms account for less than 5% of all cerebral aneurysms. They have a high risk of rupture and are associated with threatening clinical outcomes compared with anterior circulation aneurysms. METHOD: The endoscopic endonasal transclival approach (EETA) was used. During the temporary clipping, the neck of the aneurysm was dissected, and a permanent clip was applied. The repair of the skull base defect was carried out with the nasoseptal mucoperiosteal flap on the vascular pedicle. CONCLUSION: The EETA is a feasible alternative for the clipping of the medially located ruptured vertebral artery aneurysm. EETA can be recommended for centers with a large volume of cerebrovascular and endoscopic neurosurgical procedures.

Transpalpebral approach for microsurgical clipping of an unruptured basilar apex aneurysm: case report and literature review.

BACKGROUND AND IMPORTANCE: The supraorbital "keyhole" approach has been described for the treatment of basilar artery aneurysms. Transpalpebral approach (TPA) is an alternative minimally invasive route to aneurysms of the Circle of Willis with excellent functional and cosmetic outcomes. CLINICAL PRESENTATION: 53-years-old female who presented with an incidentally found 6.3 mm BA aneurysm with 3.1 mm neck diameter, admitted to our department of neurovascular surgery. Clipping was performed through TPA, with endoscope assistance and intraoperative ICG angiography. The patient's postoperative course was uneventful and was discharged home on postoperative day 5 without any complications. CONCLUSION: First time in the literature described keyhole TPA with eyelid incision to BA aneurysm. TPA is technically difficult and requires some experience to work through deep and limited surgical corridor. This technique can be good alternative to traditional fronto-lateral, supraorbital keyhole craniotomies.

Transpalpebral approach in skull base surgery: how I do it.

BACKGROUND: Keyhole surgery has been actively developing in the last two decades. Modern neuroimaging, preoperative individual planning, and innovative neurosurgical equipment allow us to operate through mini craniotomy with minimization of approach-related complications. METHOD: Preoperative planning is very critical. After the patient positioning, skin incision, craniotomy, and dura incision are performed. Intradural lesion is reached with standard microneurosurgical technique. A watertight dura closure is important. CONCLUSION: Transpalpebral approach can be good alternative to traditional, extended fronto-lateral craniotomies with excellent cosmetic and functional outcomes. Adequate selection of patients is important.

Microsurgical Clip Reconstruction of a True Posterior Communicating Artery Aneurysm.

Approximately 25% of intracranial aneurysms originate at the internal carotid artery and posterior communicating artery (PCoA) junction.1 In contrast to typical PCoA aneurysms, which are usually saccular, a subset known as true PCoA aneurysms arise directly from the PCoA. These represent about 1.3% of all intracranial aneurysms and 6.8% of PCoA aneurysms.1 The first report of a true PCoA aneurysm was in 1979.2Video 1 illustrates the microsurgical clipping of a true PCoA aneurysm in a 27-year-old man with subarachnoid hemorrhage and left-sided ophthalmoplegia. Computed tomography angiography revealed a large true patient consent, Our surgical strategy included 1) an extended pterional approach, 2) early brain relaxation through basal cisterns and third ventricle opening, 3) Sylvian fissure dissection, 4) partial uncus resection, 5) tracing the PCoA to the aneurysm, 6) pilot clipping and thrombectomy, and 7) careful aneurysm dissection and definitive clipping. The patient had an uncomplicated recovery and was discharged on postoperative day 5 with resolved third nerve dysfunction. A literature review from 2022 documented only 47 cases of true PCoA aneurysms, predominantly manifesting with rupture.3 Some studies suggest that these aneurysms may have a higher rupture risk than typical internal carotid artery-PCoA junction aneurysms.4 Microsurgical clipping is a primary treatment, often in cases associated with a fetal posterior cerebral artery variant.5 Ensuring the patency of the PCoA and thalamoperforating arteries is crucial, with careful visualization of the clip's distal ends to avoid impacting nearby neurovascular structures.

Bax/Mcl-1 balance affects neutrophil survival in intermittent hypoxia and obstructive sleep apnea: effects of p38MAPK and ERK1/2 signaling.

BACKGROUND: Prolonged neutrophil survival is evident in various cardiovascular and respiratory morbidities, in hypoxic conditions in-vitro and in patients with obstructive sleep apnea (OSA) characterized by nightly intermittent hypoxia (IH). This may lead to persistent inflammation, tissue injury and dysfunction. We therefore investigated by a translational approach the potential contribution of the intrinsic stress-induced mitochondrial pathway in extending neutrophil survival under IH conditions. Thus, neutrophils of healthy individuals treated with IH in-vitro and neutrophils of OSA patients undergoing nightly IH episodes in-vivo were investigated. Specifically, the balance between pro-apoptotic Bax and anti-apoptotic Mcl-1 protein expression, and the potential involvement of p38MAPK and ERK1/2 signaling pathways in the control of Mcl-1 expression were investigated. METHODS: Purified neutrophils were exposed to IH and compared to normoxia and to sustained hypoxia (SH) using a BioSpherix-OxyCycler C42 system. Bax and Mcl-1 levels, and p38MAPK and ERK1/2 phosphorylation were determined by western blotting. Also, Bax/Mcl-1 expression and Bax translocation to the mitochondria were assessed by confocal microscopy in pre-apoptotic neutrophils, before the appearance of apoptotic morphology. Co-localization of Bax and mitochondria was quantified by LSM 510 CarlZeiss MicroImaging using Manders Overlap Coefficient. A paired two-tailed t test, with Bonferroni correction for multiple comparisons, was used for statistical analysis. RESULTS: Compared to normoxia, IH and SH up-regulated the anti-apoptotic Mcl-1 by about 2-fold, down-regulated the pro-apoptotic Bax by 41% and 27%, respectively, and inhibited Bax co-localization with mitochondria before visible morphological signs of apoptosis were noted. IH induced ERK1/2 and p38MAPKs phosphorylation, whereas SH induced only p38MAPK phosphorylation. Accordingly, both ERK and p38MAPK inhibitors attenuated the IH-induced Mcl-1 increase. In SH, only p38MAPK inhibition decreased Mcl-1 expression. Similar to neutrophils of healthy subjects exposed to IH (0.97± 0.2), in OSA neutrophils, Bax/Mcl-1 ratio was significantly lower compared to normoxic controls (1.0±0.5 vs.1.99±0.3, p=0.015), and Bax did not co-localize with mitochondria. CONCLUSIONS: These findings suggest that decreased Bax/Mcl-1 balance promotes neutrophil survival in IH in-vitro as well as in OSA patients. Moreover, Bax/Mcl-1 protein function in IH and SH might be regulated by different signal transduction pathways, highlighting a novel regulatory function through ERK1/2 signaling in IH.

Fermi surface chirality induced in a TaSe2 monosheet formed by a Ta/Bi2Se3 interface reaction.

Spin-momentum locking in topological insulators and materials with Rashba-type interactions is an extremely attractive feature for novel spintronic devices and is therefore under intense investigation. Significant efforts are underway to identify new material systems with spin-momentum locking, but also to create heterostructures with new spintronic functionalities. In the present study we address both subjects and investigate a van der Waals-type heterostructure consisting of the topological insulator Bi2Se3 and a single Se-Ta-Se triple-layer (TL) of H-type TaSe2 grown by a method which exploits an interface reaction between the adsorbed metal and selenium. We then show, using surface x-ray diffraction, that the symmetry of the TaSe2-like TL is reduced from D3h to C3v resulting from a vertical atomic shift of the tantalum atom. Spin- and momentum-resolved photoemission indicates that, owing to the symmetry lowering, the states at the Fermi surface acquire an in-plane spin component forming a surface contour with a helical Rashba-like spin texture, which is coupled to the Dirac cone of the substrate. Our approach provides a route to realize chiral two-dimensional electron systems via interface engineering in van der Waals epitaxy that do not exist in the corresponding bulk materials.

Geographic and Temporal Variability of Hepatitis E Virus Circulation in the Russian Federation.

The factors influencing hepatitis E virus (HEV) circulation remain largely unexplored. We investigated HEV seroprevalence in humans and the prevalence of infection in farm pigs and rabbits in different regions of the Russian Federation, as well as the genetic diversity and population dynamics of the HEV. The anti-HEV IgG antibody detection rates in the general population increase significantly with age, from 1.5% in children and adolescents under 20 years old to 4.8% in adults aged between 20 and 59 years old to 16.7% in people aged 60 years and older. HEV seroprevalence varies between regions, with the highest rate observed in Belgorod Region (16.4% compared with the national average of 4.6%), which also has the country's highest pig population. When compared with the archival data, both increases and declines in HEV seroprevalence have been observed within the last 10 years, depending on the study region. Virus shedding has been detected in 19 out of the 21 pig farms surveyed. On one farm, the circulation of the same viral strain for five years was documented. All the human and animal strains belonged to the HEV-3 genotype, with its clade 2 sequences being predominant in pigs. The sequences are from patients, pigs, and sewage from pig farms clustered together, suggesting a zoonotic infection in humans and possible environmental contamination. The HEV-3 population size that was predicted using SkyGrid reconstruction demonstrated exponential growth in the 1970s-1990s, with a subsequent decline followed by a short rise around the year 2010, the pattern being similar to the dynamics of the pig population in the country. The HEV-3 reproduction number (Re) that was predicted using birth-death skyline analysis has fluctuated around 1 over the past 20 years in Russia but is 10 times higher in Belgorod Region. In conclusion, the HEV-3 circulation varies both geographically and temporally, even within a single country. The possible factors contributing to this variability are largely related to the circulation of the virus among farm pigs.

Molecular pathways of spontaneous and TNF-{alpha}-mediated neutrophil apoptosis under intermittent hypoxia.

Apoptosis of polymorphonuclear cells (PMNs) is a fundamental mechanism to halt inflammation. It limits the lifespan of PMNs and thereby decreases tissue injury. In PMNs, unlike in other cells, hypoxia profoundly inhibits apoptosis. However, most studies investigating hypoxic effects on the functioning of PMN focus on acute or chronic sustained hypoxia. Thus, the mechanisms by which intermittent hypoxia (IH) affects PMN apoptosis are not known. Flow cytometry and Western blotting were used to evaluate mechanisms of constitutive and TNF-α-mediated PMN apoptosis in IH. The levels of NF-κB, p38 mitogen-activated protein kinase (MAPK), TNF receptor-2 (TNFR-2), intracellular IL-8 and its surface receptor CXCR2, were determined. Specific NF-κB (gliotoxin and parthenolide) and p38MAPK (SB202190) inhibitors were also used. TNF-α-mediated PMN apoptosis was concentration-dependent; low concentration increased PMN survival, whereas higher concentrations accelerated apoptosis. However, at all TNF-α concentrations, PMN survival was higher after four IH cycles than in normoxia. However, increasing the IH cycles to six abolished the pro-apoptotic/anti-apoptotic effects of TNF-α. Also, IH increased TNRF2 expression, nuclear NF-κB translocation, p38MAPK phosphorylation, and expression of IL-8 and CXCR2. The NF-κB inhibitors gliotoxin and parthenolide increased apoptosis and decreased IL-8 and CXCR2 expression. Also, the p38MAPK inhibitor SB202190 increased apoptosis and decreased IL-8 expression but had no effect on CXCR2 expression. Collectively, these findings provide insights into the mechanisms that prolong PMN survival after IH exposure and demonstrate the essential role played by NF-κB, the p38MAPK signaling pathway, and downstream genes in this process.

Functional tongue and floor of mouth reconstruction with a chimeric flap after total glossectomy.

PURPOSE: Presently, the functional reconstruction of the tongue in patients after subtotal or total glossectomy with the removal of the oral floor muscles and spearing of the larynx remains a complicated and unsolved issue. The aim of this case is to describe a method reconstruction of the tongue in patients after total glossectomy with the removal of the oral floor muscles using the chimeric latissimus dorsi and serratus anterior free flap (chimeric LD + SA flap) with motor innervation. METHODS: A 62-year-old woman with advanced cancer of the oral cavity was submitted to total glossectomy and then reconstruction with a chimeric LD + SA flap. With this method reconstruction of the tongue was made the creation a large mound (neotongue) lateral to the mandibular arch which can easily reach the palatal arch and also was made suspension of the larynx is essential given the ablative loss of supra-hyoid attachments. RESULTS: Our preliminary experience shows that this flap is a good reconstructive option for total glossectomy with the removal of the oral floor muscles and with larynx preservation. Functional and objective evaluation of the tongue reconstructed with chimeric LD + SA free flap requires further and standardized evaluation.

Successful microsurgical clipping of ruptured fusiform aneurysm of the anterior cerebral artery. Case report and review of the literature.

BACKGROUND: Fusiform aneurysms (FA) of the anterior cerebral artery (ACA) are found rarely. The common clinical presentation is a subarachnoid hemorrhage (SAH). Surgery is the main treatment to prevent rebleeding. CASE DESCRIPTION: The authors present a case report of the ruptured FA of the ACA. The presented case demonstrates the successful microsurgical clipping of the fusiform ACA aneurysm. CONCLUSION: A1-segment FA can lead to SAH with poor prognosis. The main goal of surgical treatment is to prevent rebleeding. Direct microsurgical clipping is one of the surgical options.

Transpalpebral Approach for Microsurgical Removal of Tuberculum Sellae Meningiomas.

BACKGROUND: The evolution of skull base approaches associated with individualization of surgical corridor and minimizing the collateral damage. Achieving the radical removal of tumor and preserving the neurological status of the patient is possible, both with the traditional approaches and keyhole approaches. Our work presents experience using the transpalpebral approach (TPA) for microsurgical removal of tuberculum sellae meningioma (TSM). MATERIALS AND METHODS: A total of 15 patients with meningiomas underwent microsurgical removal of TSM through TPA. Ten patients were women and five were men. The standard preoperative diagnostic protocol includes magnetic resonance imaging with contrast enhancement, brain computed tomography for neuronavigation. We assess surgical complications, functional and cosmetic outcomes, and surgical parameters, including the time of surgery and intraoperative blood loss. RESULTS: Visual impairment was finding in 100% patients, including slight decrease of vision (46,7%, seven patients), partial vision field loss (six patients, 40%), and serious visual impairment (two patients 13.3%). Visual improvement was noted in ten cases (66.7%), there was no improvement in four cases (26.7%), and one case (6.6%) had transient visual worsening for 4 days and slow improvement in 1 month. Headache disappeared in three patients (50%). There were no cases of cerebrospinal fluid leak. Transient frontal hypoesthesia was noted in all patients (100%) without permanent deficit. Transient palsy of the frontal muscle was noted in four patients for 4-6 months. Histological examination revealed WHO Grade I meningioma in 14 cases and in 1 case WHO Grade II meningioma. No deaths were identified in follow-up at 12 months. The average value of the Modified Rankin Scale was 1.4. The mean length of stay in hospital was 5. CONCLUSION: TPA is technically difficult and requires some experience to work in deep structures in a small surgical corridor. This technique can be good alternative to traditional fronto-lateral, supraorbital keyhole craniotomies, and endoscopic endonasal approaches.

Mutation profiling in eight cases of vagal paragangliomas.

BACKGROUND: Vagal paragangliomas (VPGLs) belong to a group of rare head and neck neuroendocrine tumors. VPGLs arise from the vagus nerve and are less common than carotid paragangliomas. Both diagnostics and therapy of the tumors raise significant challenges. Besides, the genetic and molecular mechanisms behind VPGL pathogenesis are poorly understood. METHODS: The collection of VPGLs obtained from 8 patients of Russian population was used in the study. Exome library preparation and high-throughput sequencing of VPGLs were performed using an Illumina technology. RESULTS: Based on exome analysis, we identified pathogenic/likely pathogenic variants of the SDHx genes, frequently mutated in paragangliomas/pheochromocytomas. SDHB variants were found in three patients, whereas SDHD was mutated in two cases. Moreover, likely pathogenic missense variants were also detected in SDHAF3 and SDHAF4 genes encoding for assembly factors for the succinate dehydrogenase (SDH) complex. In a patient, we found a novel variant of the IDH2 gene that was predicted as pathogenic by a series of algorithms used (such as SIFT, PolyPhen2, FATHMM, MutationTaster, and LRT). Additionally, pathogenic/likely pathogenic variants were determined for several genes, including novel genes and some genes previously reported as associated with different types of tumors. CONCLUSIONS: Results indicate a high heterogeneity among VPGLs, however, it seems that driver events in most cases are associated with mutations in the SDHx genes and SDH assembly factor-coding genes that lead to disruptions in the SDH complex.

Delayed neutrophil apoptosis in patients with sleep apnea.

RATIONALE: Obstructive sleep apnea (OSA), characterized by intermittent hypoxia/reoxygenation (IHR), is associated with atherosclerosis. Polymorphonuclear leukocytes (PMNs) are implicated in atherogenesis by producing oxidizing radicals and proteolytic enzymes during PMN-endothelium interactions. PMN apoptosis is a fundamental, injury-limiting mechanism, which prevents their destructive potential. OBJECTIVES: To determine whether PMN apoptosis and expression of adhesion molecules are affected by OSA and IHR in vitro. METHODS: Apoptosis and expression of adhesion molecules were assessed in whole blood PMNs by flow cytometry, verified by various culture conditions, and morphology. These were complemented by exposing whole blood and purified PMNs to IHR and to sustained hypoxia in vitro. MEASUREMENTS AND MAIN RESULTS: This study demonstrates for the first time that, in patients with moderate to severe OSA, PMN apoptosis is delayed. Apoptosis was attenuated in patients with an apnea-hypopnea index (AHI) of more than 15, determined by decreased expression of low-CD16/annexin-V-positive PMNs, by lowered caspase-3 activity and nuclear condensation. Concomitantly, selectin-CD15 expression was increased in a severity-dependent manner in patients with moderate to severe OSA having an AHI greater than 15. The percentage of apoptotic PMNs was negatively correlated with OSA severity, determined by AHI, and positively with CD15 expression. In nasal continuous positive airway pressure-treated patients, CD15 expression was attenuated and low CD16 was increased, whereas omitting nasal continuous positive airway pressure for a single night increased CD15 expression and decreased the percentage of low CD16. IHR in vitro delayed PMN apoptosis as well. CONCLUSIONS: Decreased apoptosis and increased expression of adhesion molecules were noted in OSA PMNs. Although adhesion molecules may facilitate increased PMN-endothelium interactions, decreased apoptosis may further augment these interactions and facilitate free radical and proteolytic enzyme release.

A bismuth triiodide monosheet on Bi2Se3(0001).

A stable BiI3 monosheet has been grown for the first time on the (0001) surface of the topological insulator Bi2Se3 as confirmed by scanning tunnelling microscopy, surface X-ray diffraction, and X-ray photoemision spectroscopy. BiI3 is deposited by molecular beam epitaxy from the crystalline BiTeI precursor that undergoes decomposition sublimation. The key fragment of the bulk BiI3 structure, [Formula: see text][I-Bi-I] layer of edge-sharing BiI6 octahedra, is preserved in the ultra-thin film limit, but exhibits large atomic relaxations. The stacking sequence of the trilayers and alternations of the Bi-I distances in the monosheet are the same as in the bulk BiI3 structure. Momentum resolved photoemission spectroscopy indicates a direct band gap of 1.2 eV. The Dirac surface state is completely destroyed and a new flat band appears in the band gap of the BiI3 film that could be interpreted as an interface state.

Mutational load in carotid body tumor.

BACKGROUND: Carotid body tumor (CBT) is a rare neoplasm arising from paraganglion located near the bifurcation of the carotid artery. There is great intra-tumor heterogeneity, and CBT development could be associated with both germline and somatic allelic variants. Studies on the molecular genetics of CBT are limited, and the molecular mechanisms of its pathogenesis are not fully understood. This work is focused on the estimation of mutational load (ML) in CBT. METHODS: Using the NextSeq 500 platform, we performed exome sequencing of tumors with matched lymph node tissues and peripheral blood obtained from six patients with CBT. To obtain reliable results in tumors with low ML, we developed and successfully applied a complex approach for the analysis of sequencing data. ML was evaluated as the number of somatic variants per megabase (Mb) of the target regions covered by the Illumina TruSeq Exome Library Prep Kit. RESULTS: The ML in CBT varied in the range of 0.09-0.28/Mb. Additionally, we identified several pathogenic/likely pathogenic somatic and germline allelic variants across six patients studied (including TP53 variants). CONCLUSIONS: Using the developed approach, we estimated the ML in CBT, which is much lower than in common malignant tumors. Identified variants in known paraganglioma/pheochromocytoma-causative genes and novel genes could be associated with the pathogenesis of CBT. The obtained results expand our knowledge of the mutation process in CBT as well as the biology of tumor development.

Development and Identification of a Novel Subpopulation of Human Neutrophil-derived Giant Phagocytes In Vitro.

Neutrophils (PMN) are best known for their phagocytic functions against invading pathogens and microorganisms. They have the shortest half-life amongst leukocytes and in their non-activated state are constitutively committed to apoptosis. When recruited to inflammatory sites to resolve inflammation, they produce an array of cytotoxic molecules with potent antimicrobial killing. Yet, when these powerful cytotoxic molecules are released in an uncontrolled manner they can damage surrounding tissues. In recent years however, neutrophil versatility is increasingly evidenced, by demonstrating plasticity and immunoregulatory functions. We have recently identified a new neutrophil-derived subpopulation, which develops spontaneously in standard culture conditions without the addition of cytokines/growth factors such as granulocyte colony-stimulating factor (GM-CSF)/interleukin (IL)-4. Their phagocytic abilities of neutrophil remnants largely contribute to increase their size immensely; therefore they were termed giant phagocytes (Gϕ). Unlike neutrophils, Gϕ are long lived in culture. They express the cluster of differentiation (CD) neutrophil markers CD66b/CD63/CD15/CD11b/myeloperoxidase (MPO)/neutrophil elastase (NE), and are devoid of the monocytic lineage markers CD14/CD16/CD163 and the dendritic CD1c/CD141 markers. They also take-up latex and zymosan, and respond by oxidative burst to stimulation with opsonized-zymosan and PMA. Gϕ also express the scavenger receptors CD68/CD36, and unlike neutrophils, internalize oxidized-low density lipoprotein (oxLDL). Moreover, unlike fresh neutrophils, or cultured monocytes, they respond to oxLDL uptake by increased reactive oxygen species (ROS) production. Additionally, these phagocytes contain microtubule-associated protein-1 light chain 3B (LC3B) coated vacuoles, indicating the activation of autophagy. Using specific inhibitors it is evident that both phagocytosis and autophagy are prerequisites for their development and likely NADPH oxidase dependent ROS. We describe here a method for the preparation of this new subpopulation of long-lived, neutrophil-derived phagocytic cells in culture, their identification and their currently known characteristics. This protocol is essential for obtaining and characterizing Gϕ in order to further investigate their significance and functions.

Chromosome morphometry in opisthorchiid species (Platyhelminthes, Trematoda).

Few existing studies have dealt with cytogenetics in trematodes, largely due to the attendant technical difficulty of chromosome preparation. We performed a comparative analysis of chromosomes in five opistorchiid species, including Opisthorchis felineus Rivolta, 1884, Opisthorchis viverrini Poirier, 1886, Clonorchis sinensis Cobbold, 1875, Metorchis xanthosomus Creplin 1846, and Metorchis bilis (Braun, 1790) Odening, 1962. For some of these species, no detailed morphometric description of their karyotypes has yet been published; for the karyotype of Metorchis bilis this is the first-ever description. We found that opisthorchiids, like other trematodes, are characterized by karyotypic conservatism (N=6-7) and karyotype asymmetry, although comparison of chromosome morphometric traits did reveal differences between the karyotypes of the species. Moreover, to address certain a methodological issue in trematode chromosome preparation, we analyzed how the source of chromosomal material (partenitae or mature flukes) and the chromosome preparation techniques used (air-drying and cell suspension methods) affected chromosome spreading and size, concluding that the most reliable comparative method involves comparing relative parameters (relative length, arm ratio, centromeric index) of chromosomes prepared using the same technique.

Intermittent Hypoxia Affects the Spontaneous Differentiation In Vitro of Human Neutrophils into Long-Lived Giant Phagocytes.

Previously we identified, for the first time, a new small-size subset of neutrophil-derived giant phagocytes (Gϕ) which spontaneously develop in vitro without additional growth factors or cytokines. Gϕ are CD66b(+)/CD63(+)/MPO(+)/LC3B(+) and are characterized by extended lifespan, large phagolysosomes, active phagocytosis, and reactive oxygen species (ROS) production, and autophagy largely controls their formation. Hypoxia, and particularly hypoxia/reoxygenation, is a prominent feature of many pathological processes. Herein we investigated Gϕ formation by applying various hypoxic conditions. Chronic intermittent hypoxia (IH) (29 cycles/day for 5 days) completely abolished Gϕ formation, while acute IH had dose-dependent effects. Exposure to 24 h (56 IH cycles) decreased their size, yield, phagocytic ability, autophagy, mitophagy, and gp91-phox/p22-phox expression, whereas under 24 h sustained hypoxia (SH) the size and expression of LC3B and gp91-phox/p22-phox resembled Gϕ formed in normoxia. Diphenyl iodide (DPI), a NADPH oxidase inhibitor, as well as the PI3K/Akt and autophagy inhibitor LY294002 abolished Gϕ formation at all oxygen conditions. However, the potent antioxidant, N-acetylcysteine (NAC) abrogated the effects of IH by inducing large CD66b(+)/LC3B(+) Gϕ and increased both NADPH oxidase expression and phagocytosis. These findings suggest that NADPH oxidase, autophagy, and the PI3K/Akt pathway are involved in Gϕ development.

The cumulative effect of high click rate on monaural and binaural processing in the human auditory brainstem.

OBJECTIVE: The objective of the present study was to compare the effects of high stimulus rate and click position in the train on monaurally and binaurally evoked activities in the human auditory brainstem and suggest their possible physiological mechanism. METHODS: Auditory brainstem evoked potentials (ABEPs) were recorded from 15 normally and symmetrically hearing adults from 3 channels, in response to 50dB nHL, alternating polarity clicks, presented at a rate of 21/s as well as separately to each click in a train of 10 with an interstimulus interval of 11ms. Click trains were presented at a rate of 5.13/s. The binaural interaction components (BICs) of ABEPs were derived by subtracting the response to binaural clicks from the algebraic sum of monaural responses. Single, centrally located equivalent dipoles were estimated as concise measures of the surface-summated activity of ABEPs and BICs generators. RESULTS: A significant effect of click position in the train on equivalent dipole latency of ABEP component V and on equivalent dipole magnitude of III were found. Latency was prolonged and amplitude was increased the later the click's position in the train. A significant effect of click position in the train on equivalent dipole latencies of all components of BICs was found. Latencies were prolonged if the click's position occurred later in the train, with most of the latency shift achieved by the third click in the train for the first major BIC and by the seventh click for other BIC components. No significant effects on equivalent dipole magnitudes of BICs were found. No significant effect of click position in the train on orientation of any of the equivalent dipoles of ABEP or BIC was found. CONCLUSIONS: The progressive prolongation of latency of ABEP and BIC components with advancing position in the train may be attributed to cumulatively decreased synaptic efficacy at high stimulus rates, resulting in prolonged synaptic delays along the auditory pathway. The paradoxic enhancement of ABEP dipole III magnitude with advancing click position in the train may reflect higher sensitivity of inhibitory brainstem neurons to increased stimulus rate, resulting in disinhibition. The absence of significant effects on BIC dipole magnitudes may reflect the amplifying effect of divergence in the ascending auditory pathway, as has been observed for the monaurally evoked ABEP components from the upper pons.

The combined effects of forward masking by noise and high click rate on monaural and binaural human auditory nerve and brainstem potentials.

OBJECTIVE: To study effects of forward masking and rapid stimulation on human monaurally- and binaurally-evoked brainstem potentials and suggest their relation to synaptic fatigue and recovery and to neuronal action potential refractoriness. METHODS: Auditory brainstem evoked potentials (ABEPs) were recorded from 12 normally- and symmetrically hearing adults, in response to each click (50 dB nHL, condensation and rarefaction) in a train of nine, with an inter-click interval of 11 ms, that followed a white noise burst of 100 ms duration (50 dB nHL). Sequences of white noise and click train were repeated at a rate of 2.89 s(-1). The interval between noise and first click in the train was 2, 11, 22, 44, 66 or 88 ms in different runs. ABEPs were averaged (8000 repetitions) using a dwell time of 25 micros/address/channel. The binaural interaction components (BICs) of ABEPs were derived and the single, centrally located equivalent dipoles of ABEP waves I and V and of the BIC major wave were estimated. RESULTS: The latencies of dipoles I and V of ABEP, their inter-dipole interval and the dipole magnitude of component V were significantly affected by the interval between noise and clicks and by the serial position of the click in the train. The latency and dipole magnitude of the major BIC component were significantly affected by the interval between noise and clicks. Interval from noise and the click's serial position in the train interacted to affect dipole V latency, dipole V magnitude, BIC latencies and the V-I inter-dipole latency difference. Most of the effects were fully apparent by the first few clicks in the train, and the trend (increase or decrease) was affected by the interval between noise and clicks. CONCLUSIONS: The changes in latency and magnitude of ABEP and BIC components with advancing position in the click train and the interactions of click position in the train with the intervals from noise indicate an interaction of fatigue and recovery, compatible with synaptic depletion and replenishing, respectively. With the 2 ms interval between noise and the first click in the train, neuronal action potential refractoriness may also be involved.