Search

Objectives. The recent expansion of eligibility for cochlear implantation (CI) by the U.S. Food and Drug Administration (FDA) to include infants as young as 9 months has reignited debates concerning the clinically appropriate cut-off age for pediatric CI. Our study compared the early postoperative trajectories of receptive and expressive language development in children who received CI before 9 months of age with those who received it between 9 and 12 months. This study involved a unique pediatric cohort with documented etiology, where the timing of CI was based on objective criteria and efforts were made to minimize the influence of parental socioeconomic status. Methods. A retrospective review of 98 pediatric implantees recruited at a tertiary referral center was conducted. The timing of CI was based on auditory and language criteria focused on the extent of delay corresponding to the bottom 1st percentile of language development among age-matched controls, with patients categorized into very early (CI at 9 months), in children with profound deafness who have a clear deafness etiology and language development delays (

Purpose Lithotomy position has been widely used in the various urologic surgery. Occasionally sensory and motor problems of the lower extremities are occurred due to the lithotomy position and these deficits may be related with sciatic nerve injury (SNI). Inflammatory process is a factor to induce functional impairment after SNI. Therefore, we evaluated the role of adenosine A2A receptor agonists, polydeoxyribonucleotide (PDRN) showing anti-inflammatory effect on locomotor function following SNI in rats. Methods Sciatic nerve was compressed with surgical clips for 1 minute after exposing of right sciatic nerve. After 3 days of SNI, PDRN (2, 4, and 8 mg/kg) was applied to the damaged area of sciatic nerve once daily for 10 days. Walking track analysis was conducted for locomotor function and plantar test was performed for thermal pain sensitivity. Level of cyclic adenosine-3´,5´-monophosphate (cAMP) were measured using enzyme-linked immunosorbent assay. Western blot analysis was performed for tumor necrosis factor (TNF)-α, interleukin (IL)-1β, cAMP response element binding protein (CREP), vascular endothelial growth factor (VEGF). Immunofluorescence for neurofilament was also conducted. Results Locomotor function was decreased and thermal pain sensitivity was increased by SNI. SNI enhanced proinflammatory cytokines’ production, such as TNF-α and IL-1β, while suppressed CREP phosphorylation and cAMP level. SNI also reduced the expression of VEGF and neurofilaments. However, treatment with PDRN inhibited proinflammatory cytokines’ production and upregulated CREP phosphorylation and cAMP expression. PDRN also enhanced the expression of VEGF and neurofilaments. As a result, PDRN improved locomotor function and alleviated thermal hyperalgesia after SNI. Conclusions PDRN has shown potential to be used as an effective treatment for neuropathic pain.

Abstract POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.

Abstract Branchio-oto-renal (BOR)/branchio-otic (BO) syndrome is a rare disorder and exhibits clinically heterogenous phenotypes, marked by abnormalities in the ear, branchial arch, and renal system. Sporadic cases of atypical BOR/BO syndrome have been recently reported; however, evidence on genotype–phenotype correlations and molecular mechanisms of those cases is lacking. We herein identified five SIX1 heterozygous variants (c.307dupC:p.Leu103Profs*51, c.373G>A:p.Glu125Lys, c.386_391del:p.Tyr129_Cys130del, c.397_399del:p.Glu133del, and c.501G>C:p.Gln167His), including three novel variants, through whole-exome sequencing in five unrelated Korean families. All eight affected individuals with SIX1 variants displayed non-syndromic hearing loss (DFNA23) or atypical BO syndrome. The prevalence of major and minor criteria for BOR/BO syndrome was significantly reduced among individuals with SIX1 variants, compared to 15 BOR/BO syndrome families with EYA1 variants. All SIX1 variants interacted with the EYA1 wild-type; their complexes were localized in the nucleus except for the p.Leu103Profs*51 variant. All mutants also showed obvious but varying degrees of reduction in DNA binding affinity, leading to a significant decrease in transcriptional activity. This study presents the first report of SIX1 variants in South Korea, expanding the genotypic and phenotypic spectrum of SIX1 variants, characterized by DFNA23 or atypical BO syndrome, and refines the diverse molecular aspects of SIX1 variants according to the EYA1–SIX1–DNA complex theory.

Abstract The 2018 Hearing Loss Expert Panel (HL-EP)-specific guidelines specified from the universal 2015 ACMG/AMP guidelines are proposed to be used in genetic HL, which prompted this study. A genetic HL cohort comprising 135 unrelated probands with available exome sequencing data was established. Overall, 169 variants were prioritized as candidates and interpreted using the 2015 ACMG/AMP and 2018 HL-EP guidelines. Changes in rule application and variant classification between the guidelines were compared. The concordance rate of variant classification of each variant between the guidelines was 71.60%, with significant difference. The proportion of pathogenic variants increased from 13.02% (2015) to 29.59% (2018). Variant classifications of autosomal recessive (AR) variants that previously belonged to VUS or likely pathogenic in the 2015 guidelines were changed toward pathogenic in the 2018 guidelines more frequently than those of autosomal dominant variants (29.17% vs. 6.38%, P = 0.005). Stratification of the PM3 and PP1 rules in the 2018 guidelines led to more substantial escalation than that in the 2015 guidelines. We compared the disease-specific guidelines (2018) with the universal guidelines (2015) using real-world data. Owing to the sophistication of case-level data, the HL-specific guidelines have more explicitly classified AR variants toward “likely pathogenic” or “pathogenic”, serving as potential references for other recessive genetic diseases.

Abstract Determining the etiology of severe-to-profound sensorineural hearing loss (SP-SNHL) in pediatric subjects is particularly important in aiding the decision for auditory rehabilitation. We aimed to update the etiologic spectrum of pediatric SP-SNHL by combining internal auditory canal (IAC)-MRI with comprehensive and state-of-the-art genetic testings. From May 2013 to September 2020, 119 cochlear implantees under the age of 15 years with SP-SNHL were all prospectively recruited. They were subjected to genetic tests, including exome sequencing, and IAC-MRI for etiologic diagnosis. Strict interpretation of results were made based on ACMG/AMP guidelines and by an experienced neuroradiologist. The etiology was determined in of 65.5% (78/119) of our cohort. If only one of the two tests was done, the etiologic diagnostic rate would be reduced by at least 21.8%. Notably, cochlear nerve deficiency (n = 20) detected by IAC-MRI topped the etiology list of our cohort, followed by DFNB4 (n = 18), DFNB1 (n = 10), DFNB9 (n = 10) and periventricular leukomalacia associated with congenital CMV infection (n = 8). Simultaneous application of state-of-the-art genetic tests and IAC-MRI is essential for etiologic diagnosis, and if lesions of the auditory nerve or central nerve system are carefully examined on an MRI, we can identify the cause of deafness in more than 65% of pediatric SP-SNHL cases.

Abstract Autoimmune and autoinflammatory inner ear diseases (AIED/AID) are characterized by the symptom of sensorineural hearing loss (SNHL). To date, standardized diagnostic tools for AIED/AID are lacking, and clinically differentiating AIED/AID from chronic otitis media (COM) with SNHL is challenging. This retrospective study aimed to construct a magnetic resonance imaging (MRI)-based decision tree using classification and regression tree (CART) analysis to distinguish AIED/AID from COM. In total, 67 patients were enrolled between January 2004 and October 2019, comprising AIED/AID (n = 18), COM (n = 24), and control groups (n = 25). All patients underwent 3 T temporal bone MRI, including post-contrast T1-weighted images (postT1WI) and post-contrast FLAIR images (postFLAIR). Two radiologists evaluated the presence of otomastoid effusion and inner ear contrast-enhancement on MRI. A CART decision tree model was constructed using MRI features to differentiate AIED/AID from COM and control groups, and diagnostic performance was analyzed. High-intensity bilateral effusion (61.1%) and inner ear enhancement (postFLAIR, 93.8%; postT1WI, 61.1%) were the most common findings in the AIED/AID group. We constructed two CART decision tree models; the first used effusion amount as the first partitioning node and postT1WI-inner ear enhancement as the second node, whereas the second comprised two partitioning nodes with the degree of postFLAIR-enhancement of the inner ear. The first and second models enabled distinction of AIED/AID from COM with high specificity (100% and 94.3%, respectively). The amount of effusion and the degree of inner ear enhancement on MRI may facilitate the distinction between AIED/AID and COM with SNHL using decision tree models, thereby contributing to early diagnosis and intervention.

Abstract Variant prioritization of exome sequencing (ES) data for molecular diagnosis of sensorineural hearing loss (SNHL) with extreme etiologic heterogeneity poses a significant challenge. This study used an automated variant prioritization system (“EVIDENCE”) to analyze SNHL patient data and assess its diagnostic accuracy. We performed ES of 263 probands manifesting mild to moderate or higher degrees of SNHL. Candidate variants were classified according to the 2015 American College of Medical Genetics guidelines, and we compared the accuracy, call rates, and efficiency of variant prioritizations performed manually by humans or using EVIDENCE. In our in silico panel, 21 synthetic cases were successfully analyzed by EVIDENCE. In our cohort, the ES diagnostic yield for SNHL by manual analysis was 50.19% (132/263) and 50.95% (134/263) by EVIDENCE. EVIDENCE processed ES data 24-fold faster than humans, and the concordant call rate between humans and EVIDENCE was 97.72% (257/263). Additionally, EVIDENCE outperformed human accuracy, especially at discovering causative variants of rare syndromic deafness, whereas flexible interpretations that required predefined specific genotype–phenotype correlations were possible only by manual prioritization. The automated variant prioritization system remarkably facilitated the molecular diagnosis of hearing loss with high accuracy and efficiency, fostering the popularization of molecular genetic diagnosis of SNHL.

ObjectiveThe pathogenesis of hearing loss in autoinflammatory disorders due to activation of the inflammasome remains incompletely understood. Previously no animals expressing mutant Nlrp3 (NOD-, LRR- and pyrin domain-containing protein 3) survived to an age when hearing evaluation was possible due to embryonic lethality. We aimed to establish a novel mouse model that manifests quantifiable hearing loss with other syndromic features due to alteration of Nlrp3 and investigate the audiologic and histopathologic phenotype in the cochlea to clarify how the genetic alterations of NLRP3 could induce autoinflammatory hearing loss.MethodsTo induce inner ear expression of the mutant Nlrp3, Nlrp3D301NneoR mice were bred with Gfi1Cre knock-in mice for conditional mutant Nlrp3 activation in the cochlea and hematopoietic cells. Hearing thresholds were measured. Hematoxylin-eosin sections of the cochlea, brain, kidney, and liver were examined under light microscopy. Immunohistochemical analyses using polyclonal anti-NLRP3 antibodies on cochlear whole-mount preparations and frozen sections were performed.ResultsWe, for the first time in the literature, established a mouse model that manifests quantifiable hearing loss due to Nlrp3 alteration. ABR recordings of Nlrp3D301NneoR/+; Gfi1Cre/+ mice, albeit with limited life expectancy, exhibited severe to profound hearing loss at postnatal day 20 (P20). There was overall overexpression of mutant Nlrp3, and mutant Nlrp3 expression was noted in the spiral prominence, the outer sulcus region (Claudius cells and outer sulcus cells), the organ of Corti, the inner sulcus, and the spiral ganglion neurons in the cochlea. The hematoxylin-eosin sections of Nlrp3D301NneoR/+; Gfi1Cre/+ mice cochleae at P12 exhibited a disorganized organ of Corti between the outer hair cells/supporting Deiters' cells and basilar membrane compared with the normal phenotype mice, leading to a collapsed Nuel's space. This morphologic feature gradually returned to normal by P15. Varying degrees of inflammation with lymphocytic infiltrations were observed in the brain, kidney, and liver.ConclusionWe report the first mutant Nlrp3 overexpression mouse model (Nlrp3D301NneoR/+; Gfi1Cre/+) that shows obvious overexpression of Nlrp3 in the cochlea, a transient developmental lag of the cochlea, and severe to profound hearing loss. We expect that this mouse line, which models human autoinflammatory hearing loss, could provide a valuable tool to elucidate the underlying pathogenic mechanism of inflammasome activation-mediated hearing loss.

Purpose Adenosine A2A receptor agonist polydeoxyribonucleotide (PDRN) possesses an anti-inflammatory effect and suppress apoptotic cell death in several disorders. In this current study, the effect of PDRN on inflammation and apoptosis in rats with Achilles tendon injury was investigated. Methods von Frey filament test and plantar test were conducted for the determination of pain threshold. Analysis of histological alterations was conducted by hematoxylin and eosin staining. Immunohistochemistry for cleaved caspase-3-positive cells and cleaved caspase-9-positive cells was done. Enzyme-linked immunoassay was used to detect the concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and cyclic adenosine-3’,5’-monophosphate (cAMP). Western blot was conducted to detect the protein levels of cAMP response element-binding protein (CREB), protein kinase A (PKA), Bcl-2-associated X (Bax), and B-cell lymphoma 2 (Bcl-2). Results PDRN treatment relieved mechanical allodynia and alleviated thermal hyperalgesia after Achilles tendon injury. TNF-α and IL-6 concentrations were decreased by PDRN application. PDRN injection significantly enhanced cAMP concentration and phosphorylated CREB versus CREB ratio, showing cAMP-PKA-CREB pathway was activated by PDRN application. PDRN treatment inhibited percentages of cleaved caspase-3-positive cells and caspase-9-posiive cells and the suppressed Bax versus Bcl-2 ratio in Achilles tendon injury rats. Conclusions PDRN is probably believed to have a good effect on pain and inflammation in the urogenital organs. PDRN may be used as a new treatment for Achilles tendon injury.

There are still debates about timing and effectiveness of cochlear implants (CI) in pediatric subjects with significant residual hearing who do not belong to traditional indication of CI. In this study, we aimed to investigate the outcomes of CI, specifically on improvement of pronunciation, among hearing-impaired children already with a substantial degree of language skills as evaluated by Categories of Auditory Perception (CAP) scores or sentence score. Our cohort comprised pediatric CI recipients from July 2018 through October 2020. Among them, cases with CAP scores of 5 or 6 preoperatively were defined as “borderline cases”. We investigated prevalence and etiologies, and compared speech evaluation data preoperatively and postoperatively at three time points (3, 6 and 9–12 months after implantation). Among 86 pediatric CI recipients, 13 subjects (15.12%) had language development that reached CAP scores of 5 or 6 before implantation. Postoperative speech evaluation data 6 months after implantation revealed significant improvement of pronunciation (Urimal Test of Articulation and Phonation scores: UTAP), Infant-Toddler Meaningful Auditory Integration Scale (IT-MAIS) and word perception scores, but not of CAP and sentence perception scores. Notably, the significant improvement of pronunciation based on UTAP scores outstripped that of other speech parameters and this continued steadily up to one-year postoperatively. The result of the study serves as evidence for what to expect from cochlear implantation in hearing-impaired children who have already achieved a substantial degree of language development in terms of CAP scores or sentence perception scores, preoperatively.

Objectives We, herein, report two novel USH2A variants from two unrelated Korean families and their clinical phenotypes, with attention to severe or more than severe sensorineural hearing loss (SNHL). Methods Two postlingually deafened subjects (SB237-461, M/46 and SB354-692, F/34) with more than severe SNHL and also with suspicion of Usher syndrome type II (USH2) were enrolled. A comprehensive audiological and ophthalmological assessments were evaluated. We conducted the whole exome sequencing and subsequent pathogenicity prediction analysis. Results We identified the following variants of USH2A from the two probands manifesting more than severe SNHL and retinitis pigmentosa (RP): compound heterozygosity for a nonsense (c.8176C>T: p.R2723X) and a missense variant (c.1823G>A: p.C608Y) in SB237, and compound heterozygosity for two frameshift variants (c.14835delT: p.S4945fs & c.13112_13115delAAAT: p.G4371fs) in SB354. Based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines, two novel variants, c.1823G>A: p.C608Y and c.14835delT: p.Ser4945fs, can be classified as “uncertain significance” and “pathogenic,” respectively. The audiogram exhibited more than severe SNHL and a down-sloping configuration, necessitating cochlear implantation. The ophthalmic examinations revealed typical features of RP. Interestingly, one proband (SB 354-692) carrying two truncating compound heterozygous variants exhibited more severe hearing loss than the other proband (SB 237-461), carrying one truncation with one missense variant. Conclusion Our results provide insight on the expansion of audiological spectrum encompassing more than severe SNHL in Korean subjects harboring USH2A variants, suggesting that USH2A should also be included in the candidate gene of cochlear implantation. A specific combination of USH2A variants causing truncating proteins in both alleles could demonstrate more severe audiological phenotype than that of USH2A variants carrying one truncating mutation and one missense mutation, suggesting a possible genotype-phenotype correlation. The understanding of audiological complexity associated with USH2A will be helpful for genetic counseling and treatment starategy.

Sensorineural hearing loss is one of the most common inherited sensory disorders. Functional classifications of deafness genes have shed light on genotype- and mechanism-based pharmacological approaches and on gene therapy strategies. In this study, we characterized the clinical phenotypes and genotypes of non-syndromic deafness caused by transcription factor (TF) gene variants, one of the functional classifications of genetic hearing loss. Of 1280 probands whose genomic DNA was subjected to molecular genetic testing, TF genes were responsible for hearing loss in 2.6%. Thirty-three pathogenic variants, including nine novel variants, accounting for non-syndromic deafness were clustered in only four TF genes (POU3F4, POU4F3, LMX1A, and EYA4), which is indicative of a narrow molecular etiologic spectrum of TF genes, and the functional redundancy of many other TF genes, in the context of non-syndromic deafness. The audiological and radiological characteristics associated with the four TF genes differed significantly, with a wide phenotypic spectrum. The results of this study reveal the genetic load of TF gene alterations among a cohort with non-syndromic hearing loss. Additionally, we have further refined the clinical profiles associated with TF gene variants as a basis for a personalized, genetically tailored approach to audiological rehabilitation.

Abstract Background While auditory neuropathy spectrum disorder (ANSD) is a heterogeneous disorder and its management quite varies depending upon the etiology, even including self-resolution, OTOF is an important molecular etiology of prelingual ANSD and has emerged as an attractive target for implementation of precision medicine in terms of timing and prognosis prediction of auditory rehabilitation. However, to date, the literature is lacking in the genotype–phenotype relationship of this gene as well as efficient molecular testing strategy in the clinic in many populations and to make things more complicated in Koreans, the most prevalent variant p.Arg1939Gln among Korean ANSD children frequently evaded detection by next generation sequencing (NGS), resulting in delayed genetic diagnosis and late cochlear implantation (CI). The aims of this study are to document the mutational and phenotypic spectrum of OTOF-related ANSD (DFNB9) in the Korean population, further establishing genotype–phenotype correlation and proposing a set of the most commonly found OTOF variants to be screened first. Methods Genetic diagnosis through the NGS-based sequencing was made on patients with ANSD in two tertiary hospitals. Genotype and phenotypes of eleven DFNB9 patients were reviewed. For data analysis, Mann–Whitney test and Fisher’s exact test were applied. Results This study disclosed four prevalent variants in Koreans: p.Arg1939Gln with an allele frequency of 40.9%, p.Glu841Lys (13.6%), p.Leu1011Pro and p.Arg1856Trp (9.1%). Three novel variants (c.4227 + 5G > C, p.Gly1845Glu, and p.Pro1931Thr) were identified. Interestingly, a significant association of p.Arg1939Gln with worse ASSR thresholds was observed despite consistently no ABR response. Ten of 11 DFNB9 patients received CI for auditory rehabilitation, showing favorable outcomes with more rapid improvement on early-CI group (age at CI ≤ 18 mo.) than late-CI group. Conclusions This study included the largest Korean DFNB9 cohort to date and proposed a set of the most frequent four OTOF variants, allowing the potential prioritization of exons during Sanger sequencing. Further, a significant association of p.Arg1939Gln homozygotes with poor residual hearing was observed. We may have to suspect p.Arg1939Gln homozygosity in cases of poor auditory thresholds in ANSD children with putative negative OTOF variants solely screened by NGS. Reciprocal feedback between bench and clinics regarding DFNB9 would complement each other.

Cerebral ischemia causes tissue death owing to occlusion of the cerebral blood vessels, and cerebral ischemia activates mitogen-activated protein kinase (MAPK) and induces secretion of pro-inflammatory cytokines. Adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), suppresses the secretion of pro-inflammatory cytokines and exhibits anti-inflammatory effect. In the current study, the therapeutic effect of PDRN on cerebral ischemia was evaluated using gerbils. For the induction of cerebral ischemia, the common carotid arteries were exposed, and then aneurysm clips were used to occlude the common carotid arteries bilaterally for 7 minutes. In the PDRN-treated groups, the gerbils were injected intraperitoneally with 0.3 mL of saline containing 8 mg/kg PDRN, per a day for 7 days following cerebral ischemia induction. In order to confirm the participation of the adenosine A2A receptor in the effects mediated by PDRN, 8 mg/kg 7-dimethyl-1-propargylxanthine (DMPX), adenosine A2A receptor antagonist, was treated with PDRN. In the current study, induction of ischemia enhanced the levels of pro-inflammatory cytokines and increased phosphorylation of MAPK signaling factors in the hippocampus and basolateral amygdala. However, treatment with PDRN ameliorated short-term memory impairment by suppressing the production of pro-inflammatory cytokines and inactivation of MAPK signaling factors in cerebral ischemia. Furthermore, PDRN treatment enhanced the concentration of cyclic adenosine-3,5'-monophosphate (cAMP) as well as phosphorylation of cAMP response element-binding protein (p-CREB). Co-treatment of DMPX and PDRN attenuated the therapeutic effect of PDRN on cerebral ischemia. Based on these findings, PDRN may be developed as the primary treatment in cerebral ischemia.

The cortical auditory evoked potential (CAEP)-based P1 component acts as a biomarker for cochlear implantation (CI) outcomes in children with auditory neuropathy spectrum disorder (ANSD). To date, early intervention primarily before the age of two years and six months of CI usage is necessary and sufficient to achieve age-appropriate cortical maturation and good prognosis. However, varying degrees of neural dyssynchrony, resulting from the etiological heterogeneity of ANSD, may preclude uniform application of this hypothesis to ensure auditory cortical maturation. Thus, a focused evaluation of those carrying OTOF variants, which may be the salient molecular etiology of prelingual ANSD, would circumvent the issue of heterogeneity. Here, we sought to provide a much better understanding of the brain perspectives (i.e., P1 maturation) in OTOF-associated ANSD subjects and set the stage for an optimal strategy to enhance language development. We conducted a preliminary study comprising 10 subjects diagnosed with OTOF-related ANSD who underwent CI by a single surgeon and subsequently underwent measurements of the P1 component. We observed that DFNB9 subjects who received CI after 2 years of age exhibited "absent" or "anomalous" P1 components that correspond to delayed language development. However, timely implantation, as early as 12 months of age per se, might be insufficient to achieve age-appropriate cortical maturation of DFNB9 in cases with six to seven months of device use. This suggests the importance of sustained rehabilitation in DFNB9 than in other etiologies. Indeed, an additional follow-up study showed that a reduction in P1 latency was linked to an improvement in auditory performance. Collectively, our results suggest that central auditory maturation and successful outcome of CI in DFNB9 may have more demanding requirements, that is, earlier implantation and more sustained rehabilitation. We believe that the current study opens a new path toward genome-based neuroimaging in the field of hearing research.

Purpose The effects of dexmedetomidine on locomotor function and thermal hyperalgesia in sciatic nerve crush injury (SNCI) were investigated using rats. Methods After exposing the right sciatic nerve, the sciatic nerve was crushed for 1 minute by a surgical clip. One day after nerve injury, dexmedetomidine (5, 25, and 50 µg/kg) was directly applied to the injured sciatic nerve once a day for 14 days. Walking track analysis was used to assess locomotor function and plantar test was conducted to assess thermal pain sensitivity. Immunohistochemistry was performed to determine the expression of c-Fos in the ventrolateral periaqueductal gray (vlPAG) and paraventricular nucleus (PVN). Western blot was used to evaluate the expression level of nerve growth factor (NGF) and myelin basic protein (MBP) in the sciatic nerve. Results SNCI resulted in deterioration of locomotor function and increased thermal pain sensitivity. The level of c-Fos expression in the PVN and vlPAG was increased and the level of NGF and MBP expression in the sciatic nerve was enhanced by SNCI. Dexmedetomidine treatment improved locomotor function and upregulated expression of NGF and MBP in the sciatic nerve of SNCI. Dexmedetomidine treatment alleviated thermal hyperalgesia and downregulated expression of c-Fos in the vlPAG and PVN after SNCI. Conclusions Dexmedetomidine may be used as a potential new treatment drug for recovery of locomotion and control of pain in peripheral nerve injury.

Purpose Benign prostatic hyperplasia (BPH) impacts quality of life in men by causing lower urinary tract symptoms. α1-Adrenoceptor (α1-AR) blockers improve lower urinary tract symptoms. We investigated the efficacy of add-on therapy with α1-AR blockers on BPH rats. Methods Rats in the drug-treated groups were orally administered each drug once a day for 30 days after orchiectomy. To induce BPH, rats were castrated and testosterone (20 mg/kg) was injected subcutaneously once per day for 30 days. Cystometry was conducted to measure voiding contraction pressure and the interval contraction time, immunohistochemistry was performed to measure c-Fos and nerve growth factor (NGF) expression in the neuronal voiding centers, and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry was used to measure nitric oxide synthase (NOS) expression. Results Orchiectomy and testosterone injection decreased voiding contraction pressure and the interval contraction time, suggesting BPH symptoms. Voiding contraction pressure and the interval contraction time were greater in the group that received the combination treatment (tamsulosin with naftopidil) than in the tamsulosin monotherapy or naftopidil monotherapy groups. c-Fos, NGF, and NOS expression in the neuronal voiding centers was enhanced by BPH induction. c-Fos, NGF, and NOS expression was suppressed by the combination treatment (tamsulosin with naftopidil) to a greater extent than was the case for tamsulosin monotherapy or naftopidil monotherapy. Conclusions Combination therapy of tamsulosin and naftopidil showed greater efficacy for the treatment of BPH than tamsulosin monotherapy or naftopidil monotherapy; therefore, combination therapy can be considered as a novel therapeutic method for BPH.

Abstract Background MYO15A variants, except those in the N-terminal domain, have been shown to be associated with congenital or pre-lingual severe-to-profound hearing loss (DFNB3), which ultimately requires cochlear implantation in early childhood. Recently, such variants have also been shown to possibly cause moderate-to-severe hearing loss. Herein, we also demonstrate that some MYO15A mutant alleles can cause postlingual onset of progressive partial deafness. Methods Two multiplex Korean families (SB246 and SB224), manifesting postlingual, progressive, partial deafness in an autosomal recessive fashion, were recruited. Molecular genetics testing was performed in two different pipelines, in a parallel fashion, for the SB246 family: targeted exome sequencing (TES) of 129 known deafness genes from the proband and whole exome sequencing (WES) of all affected subjects. Only the former pipeline was performed for the SB224 family. Rigorous bioinformatics analyses encompassing structural variations were executed to investigate any causative variants. Results In the SB246 family, two different molecular diagnostic pipelines provided exactly the same candidate variants: c.5504G > A (p.R1835H) in the motor domain and c.10245_10247delCTC (p.S3417del) in the FERM domain of MYO15A. In the SB224 family, c.9790C > T (p.Q3264X) and c.10263C > G (p.I3421M) in the FERM domain were detected as candidate variants. Conclusions Some recessive MYO15A variants can cause postlingual onset of progressive partial deafness. The phenotypic spectrum of DFNB3 should be extended to include such partial deafness. The mechanism for a milder phenotype could be due to the milder pathogenic potential from hypomorphic alleles of MYO15A or the presence of modifier genes. This merits further investigation.

Abstract Background Risk scoring systems are used to evaluate patients with upper gastrointestinal bleeding (UGIB). We compared Glasgow-Blatchford score (GBS), modified GBS (mGBS), and Pre-endoscopy Rockall score (Pre-E RS) for immediate application without endoscopic findings in predicting the need of interventions and the 30-day mortality in patients with UGIB. Methods Patients who visited the emergency room with UGIB from January 2007 to June 2016 were included. GBS, mGBS, and Pre-E RS were obtained for all patients. The area under the receiver-operating characteristic curves (AUC) was used to assess the accuracy of the scoring systems to determine the need for interventions and 30-day mortality. Also, we investigated the potential cutoff scores for predicting 30-day mortality and the need for interventions. Results In predicting the need for interventions, GBS (AUC = 0.727) and mGBS (AUC = 0.733) outperformed Pre-E RS (AUC = 0.564, P

Purpose Rocuronium bromide is a nondepolarizing neuromuscular blocking drug and has been used as an adjunct for relaxation or paralysis of the skeletal muscles, facilitation of endotracheal intubation, and improving surgical conditions during general anesthesia. However, intravenous injection of rocuronium bromide induces injection pain or withdrawal movement. The exact mechanism of rocuronium bromide-induced injection pain or withdrawal movement is not yet understood. We investigated whether rocuronium bromide treatment is involved in the induction of inflammation and pain in vascular endothelial cells. Methods For this study, calf pulmonary artery endothelial (CPAE) cells were used, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot, nitric oxide detection, and prostaglandin E2 immunoassay were conducted. Results Rocuronium bromide treatment inhibited endothelial nitric oxide synthase and suppressed nitric oxide production in CPAE cells. Rocuronium bromide activated cyclooxygenase-2, inducible nitric oxide synthase and increased prostaglandin E2 synthesis in CPAE cells. Conclusions Rocuronium bromide induced inflammation and pain in CPAE cells. Suppressing nitric oxide production and enhancing prostaglandin E2 synthesis might be associated with rocuronium bromide-induced injection pain or withdrawal movement.

Acute liver injury (ALI) causes life-threatening clinical problem, and its underlying etiology includes inflammation and apoptosis. An adenosine A2A receptor agonist, polydeoxyribonucleotide (PDRN), exhibits anti-inflammatory and anti-apoptotic effects by inhibiting the secretion of pro-inflammatory cytokines. In the current study, the protective effect of PDRN against carbon tetrachloride (CCl4)-induced ALI was investigated using mice. For the induction of ALI, mice received intraperitoneal injection of CCl4 twice over seven days. Mice from the PDRN-treated groups received an intraperitoneal injection of 200 μL saline containing PDRN (8 mg/kg), once a day for seven days, starting on day 1 after the first CCl4 injection. In order to confirm that the action of PDRN occurs through the adenosine A2A receptor, 8 mg/kg 3,7-dimethyl-1-propargylxanthine (DMPX), an adenosine A2A receptor antagonist, was treated with PDRN. Administration of CCl4 impaired liver tissue and increased the liver index and histopathologic score. The expression of pro-inflammatory cytokines was increased, and apoptosis was induced by the administration of CCl4. Administration of CCl4 activated nuclear factor-kappa B (NF-κB) and facilitated phosphorylation of signaling factors in mitogen-activated protein kinase (MAPK). In contrast, PDRN treatment suppressed the secretion of pro-inflammatory cytokines and inhibited apoptosis. PDRN treatment inactivated NF-κB and suppressed phosphorylation of signaling factors in MAPK. As a result, liver index and histopathologic score were reduced by PDRN treatment. When PDRN was treated with DMPX, the anti-inflammatory and anti-apoptotic effect of PDRN disappeared. Therefore, PDRN can be used as an effective therapeutic agent for acute liver damage.

Routine application of next-generation sequencing in clinical settings is often limited by time- and cost-prohibitive complex filtering steps. Despite the previously introduced genotyping kit that allows screening of the 11 major recurring variants of sensorineural hearing loss (SNHL) genes in the Korean population, the demand for phenotype- and variant-specific screening kits still remains. Herein, we developed a new real-time PCR-based kit (U-TOP™ HL Genotyping Kit Ver2), comprising six variants from two auditory neuropathy spectrum disorder (ANSD) genes (OTOF and ATP1A3) and five variants from three SNHL genes (MPZL2, COCH, and TMC1), with a distinct auditory phenotype, making this the first genotyping kit dedicated to ANSD. The concordance rate with Sanger sequencing, sensitivity, and specificity of this genotyping kit were all 100%, suggesting reliability. The kit not only allows timely and cost-effective identification of recurring OTOF variants, but it also allows timely detection of cochlear nerve deficiency for those without OTOF variants. Herein, we provide a clinical guideline for an efficient, rapid, and cost-effective etiologic diagnosis of prelingual ANSD. Our study provides a good example of continuing to update new key genetic variants, which will continuously be revealed through NGS, as targets for the newly developed genotyping kit.

Elongation factor Tu guanosine-5’-triphosphate (GTP) binding domain containing 2 (EFTUD2) encodes a major component of the spliceosomal GTPase and, if mutated, causes mandibulofacial dysostosis with microcephaly (MFDM; MIM#610536). Despite the increasing number of potentially pathogenic variants reported in the literature, most previous studies have relied solely on in silico prediction of the pathogenic potential of EFTUD2 variants, which may result in misclassification of the variant’s pathogenicity. Given the importance of the functional verification of EFTUD2 variants, we identified a novel splice donor site variant, c.271+1G>A of EFTUD2, whose pathogenicity was clearly verified at the RNA level using a minigene assay. A child with MFDM, mixed hearing loss, microcephaly, and a congenital cardiac defect was identified with this variant, which arose in a de novo fashion. The minigene assay showed erroneous integration of the 118 bp IVS3 of EFTUD2 exclusively among the c.271+1G>A variant clone. We first applied the minigene assay to identify the splice function of a splice site variant of EFTUD2, thereby allowing for in vitro functional verification of splice site variants in EFTUD2.

BackgroundBispectral index (BIS) monitoring reduces the cases of intraoperative awareness. Several factors can alter BIS readings without affecting the depth of anesthesia. We conducted a study to assess the impact of beach chair position (sitting position) on BIS readings.MethodsGeneral anesthesia was administered to 30 patients undergoing arthroscopic shoulder surgery. Patients were kept in neutral position (supine) for 10 minutes and BIS readings, mean arterial blood pressure, heart rate, end-tidal carbon dioxide, and end-tidal sevoflurane were recorded. Patients were then shifted to beach chair position. After 15 minutes, data were recorded.ResultsA significant decrease in BIS values (P < 0.01) associated with a position change from neutral position to beach chair position was evident.ConclusionsBIS values are significantly decreased in the beach chair position compared with the neutral position and might affect interpretation of the depth of anesthesia.

We experienced a case of deep vein thrombosis after spine surgery in the prone position with a central venous catheter (CVC). Posterior lumbar interbody fusion was performed on a 73-year-old female patient who was diagnosed with spinal stenosis. Accordingly, in the operation room under general anesthesia, two-lumen CVC were inserted into the left subclavian vein. The surgery was performed in the prone position with a Wilson frame. On the next day, there was a sudden occurrence of severe edema in the patient's left arm. By ultrasonography and computed tomography scanning, extensive deep vein thrombosis was observed in the left subclavian vein. The existence of a factor affecting blood flow such as the prone position may increase the risk of thrombus formation. Therefore, careful perioperative evaluation should be implemented.

PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

Background and Objective The aim of this study is to compare the clinical, electrophysiological (Polysomnography, PSG; Multiple Sleep Latency Test, MSLT) and biological data (HLA DQB1*0602 typing) in idiopathic hypersomnia with narcolepsy without cataplexy. Methods 80 patients with narcolepsy without cataplexy and 71 patients with idiopathic hypersomnia without a long sleep time were recruited at the Sleep Center of St. Vincent’s Hospital. MSLT data and PSG findings from the time of their diagnosis were reviewed. HLA typing was performed. Results Results indicated that the idiopathic hypersomnia group showed a significant longer mean sleep latency in MSLT compared with the narcolepsy without cataplexy group. But there was no significant difference in the Epworth Sleepiness Scale (ESS) scores between the two groups. Although HLA positivity of both groups was not statistically significant (p = 0.065), HLA positivity tended to be higher in the narcolepsy without cataplexy group than the idiopathic hypersomnia group. The number of awakenings was slightly higher in the idiopathic hypersomnia group, but there was no statistical significance. The number of spontaneous arousal and total arousal indices was not significantly different between the groups. For the PSG, the idiopathic hypersomnia group showed a significantly longer sleep latency than the narcolepsy without cataplexy group (p = 0.009). REM sleep latency (REML) was significantly shorter in the narcolepsy without cataplexy group compared to the idiopathic hypersomnia group. The percentage of REM (SREM) was significantly higher in the narcolepsy without cataplexy group, and the percentage of the wake time during sleep period (SWT) was significantly lower in the narcolepsy without cataplexy group. Conclusions There were no significant differences of subjective sleep measures such as ESS, disturbed nocturnal sleep, number of naps, age of onset of hypnagogic hallucination, and age of onset of sleep paralysis between patients with narcolepsy without cataplexy and idiopathic hypersomnia. So, the use of objective tests such as the PSG and MSLT may be inevitable for the differential diagnosis of narcolepsy without cataplexy from idiopathic hypersomnia.

CDH23 mutations have mostly been associated with prelingual severe-to-profound sensorineural hearing loss (SNHL) in either syndromic or nonsyndromic SNHL (DFNB12). Herein, we demonstrate the contribution of CDH23 mutations to postlingual nonsyndromic SNHL (NS-SNHL). We screened 32 Korean adult probands with postlingual NS-SNHL sporadically or in autosomal recessive fashion using targeted panel or whole exome sequencing. We identified four (12.5%, 4/32) potential postlingual DFNB12 families that segregated the recessive CDH23 variants, qualifying for our criteria along with rapidly progressive SNHL. Three of the four families carried one definite pathogenic CDH23 variant previously known as the prelingual DFNB12 variant in a trans configuration with rare CDH23 variants. To determine the contribution of rare CDH23 variants to the postlingual NS-SNHL, we checked the minor allele frequency (MAF) of CDH23 variants detected from our postlingual NS-SNHL cohort and prelingual NS-SNHL cohort, among the 2040 normal control chromosomes. The allele frequency of these CDH23 variants in our postlingual cohort was 12.5%, which was significantly higher than that of the 2040 control chromosomes (5.53%), confirming the contribution of these rare CDH23 variants to postlingual NS-SNHL. Furthermore, MAF of rare CDH23 variants from the postlingual NS-SNHL group was significantly higher than that from the prelingual NS-SNHL group. This study demonstrates an important contribution of CDH23 mutations to poslingual NS-SNHL and shows that the phenotypic spectrum of DFNB12 can be broadened even into the presbycusis, depending on the pathogenic potential of variants. We also propose that pathogenic potential of CDH23 variants and the clinical fate of DFNB12 may be predicted by MAF.

Background and Objective It has been reported that Streptococcal infection is probably a significant environmental trigger for narcolepsy patients from recent studies. However the relationship between the streptococcal infection and narcolepsy is not clear. The aim of this study is to explore the anti-streptolysin O (ASO) titer in narcolepsy patients and healthy control, and the associations of ASO titer levels and polysomnographic findings. Methods Sixty two narcolepsy patients and Fifty six healthy controls were recruited at the Sleep Center of St. Vincent’s Hospital. The multiple sleep latency test data and polysomnographic findings from the time of their diagnosis were reviewed. Disease duration was defined as the time between the first symptom and time of blood draw. HLA typing was also performed. Participants were tested for markers of immune response to β hemolytic streptococcus. Results Results indicated that titers of anti-streptococcal antibodies were not significantly different between patients with narcolepsy and healthy controls. There was no significant difference of ASO titer between the HLA DQB1*0602 positive group and HLA DQB1*0602 negative group. In narcolepsy with cataplexy patients, rapid eye movement sleep latency was significantly shorter in the ASO > 200 group. Conclusions There is no significant difference of ASO titers between patients with narcolepsy and healthy controls. The association between streptococcal infections and narcolepsy in Asian people may be not as significant as Caucasian people.

BackgroundVarious maneuvers are commonly used to achieve the ideal operative field necessary for successful endoscopic sinus surgery (ESS). There are a few contradictory reports on this subject and the consensus is that propofol anesthesia results in a better or similar surgical field and less or similar amount of bleeding than volatile anesthesia. The aim of this study was to compare the surgical field in patients in whom intravenous anesthesia is used as opposed to balanced general anesthesia.MethodsSixty patients undergoing ESS were randomly assigned into three groups, each of which used a different type of anesthesia: propofol/remifentanil (PRO/REM) group, sevoflurane/remifentanil (SEV/REM) group, and desflurane/remifentanil (DES/REM) group. We aimed to maintain the intraoperative mean blood pressure (MBP) at 65 mmHg and the heartrate (HR) at about 75 beats per minute. The quality of visibility of the surgical field was graded, using a validated scoring system, 60 minutes after the start of the operation.ResultsAll groups had a similar MBP and mean HR at 60 minutes after the operation started. There was no significant differences among the three groups for surgical grade score (P = 0.83).ConclusionsIn this comparative study of three anesthetic combinations (PRO/REM, SEV/REM, and DES/REM) in patients undergoing ESS with controlled BP and HR, we did not observe any significant differences in the surgical grade scores.

Huntington's chorea is a rare hereditary disorder of the nervous system. It is inherited as an autosomal dominant disorder and is characterized by progressive chorea, dementia and psychiatric disturbances. The best anesthetic technique is yet to be established for these patients with increased risk of aspiration due to involvement of pharyngeal muscles and an exaggerated response to sodium thiopental and succinylcholine. The primary goal in general anesthesia for these patients is to provide airway protection and a rapid and safe recovery. We report the anesthetic management of a 51-year-old patient with Huntington's chorea admitted for an emergency operation.

Penetrating neck injuries can be a fatal event and they are difficult to manage for both surgeons and anesthesiologists. So, adequate preoperative evaluation is important to improve the patients' outcomes, but this can not be done for hemodynamically unstable or uncooperative patient. Here we present our clinical experience with a patient with a penetrating neck injury and who was hemodynamically stable, but she was uncooperative and the knife was still embedded in her neck. The surgical exploration and bronchoscopic examination were successfully done under monitored anesthesia care.

Even though malaria has markedly reduced its global burden, it remains a serious threat to people living in or visiting malaria-endemic areas. The six Plasmodium species (Plasmodium falciparum, Plasmodium vivax, Plasmodium malariae, Plasmodium ovale curtisi, Plasmodium ovale wallikeri and Plasmodium knowlesi) are known to associate with human malaria by the Anopheles mosquito. Highlighting the dynamic nature of malaria transmission, the simian malaria parasite Plasmodium cynomolgi has recently been transferred to humans. The first human natural infection case of P. cynomolgi was confirmed in 2011, and the number of cases is gradually increasing. It is assumed that it was probably misdiagnosed as P. vivax in the past due to its similar morphological features and genome sequences. Comprehensive perspectives that encompass the relationships within the natural environment, including parasites, vectors, humans, and reservoir hosts (macaques), are required to understand this zoonotic malaria and prevent potential unknown risks to human health.

Lately, there has been a notable surge in the defense industry's efforts to develop highly advanced intelligent systems. These systems encompass sophisticated computing platforms that boast an impressive level of autonomy. However, it's important to acknowledge that these very systems are not impervious to vulnerabilities stemming from both hardware and software tampering. Within the context of this discourse, our focus of the survey is directed towards the hardware security module. This component stands out for its capability to offer a significantly heightened level of protection when compared to conventional software-based techniques. Through the lens of this paper, we embark on a comprehensive survey of Trusted Platform Module (TPM), a hardware security module, shedding light on its potential to fortify the defense against threats that emerge from various vectors of attack. [ABSTRACT FROM AUTHOR]

Plasmodium vivax, the most widespread human malaria parasite, and P. knowlesi, an emerging Plasmodium that infects humans, are the phylogenetically closest malarial species that infect humans, which may induce cross-species reactivity across most co-endemic areas in Southeast Asia. The thrombospondin-related anonymous protein (TRAP) family is indispensable for motility and host cell invasion in the growth and development of Plasmodium parasites. The merozoite-specific TRAP (MTRAP), expressed in blood-stage merozoites, is supposed to be essential for human erythrocyte invasion. We aimed to characterize MTRAPs in blood-stage P. vivax and P. knowlesi parasites and ascertain their cross-species immunoreactivity. Recombinant P. vivax and P. knowlesi MTRAPs of full-length ectodomains were expressed in a mammalian expression system. The MTRAP-specific immunoglobulin G, obtained from immune animals, was used in an immunofluorescence assay for subcellular localization and invasion inhibitory activity in blood-stage parasites was determined. The cross-species humoral immune responses were analyzed in the sera of patients with P. vivax or P. knowlesi infections. The MTRAPs of P. vivax (PvMTRAP) and P. knowlesi (PkMTRAP) were localized on the rhoptry body of merozoites in blood-stage parasites. Both anti-PvMTRAP and anti-PkMTRAP antibodies inhibited erythrocyte invasion of blood-stage P. knowlesi parasites. The humoral immune response to PvMTRAP showed high immunogenicity, longevity, and cross-species immunoreactivity with P. knowlesi. MTRAPs are promising candidates for development of vaccines and therapeutics against vivax and knowlesi malaria. [ABSTRACT FROM AUTHOR]

The zoonotic malaria parasite Plasmodium knowlesi is an important public health concern in Southeast Asia. Invasion of host erythrocytes is essential for parasite growth, and thus, understanding the repertoire of parasite proteins that enable this process is vital for identifying vaccine candidates and how some species are able to cause zoonotic infection. Merozoite surface protein 1 (MSP1) is found in all malaria parasite species and is perhaps the most well-studied as a potential vaccine candidate. While MSP1 is encoded by a single gene in P. falciparum, all other human infective species (P. vivax, P. knowlesi, P. ovale, and P. malariae) additionally encode a divergent paralogue known as MSP1P, and little is known about its role or potential functional redundancy with MSP1. We, therefore, studied the function of P. knowlesi merozoite surface protein 1 paralog (PkMSP1P), using both recombinant protein and CRISPR-Cas9 genome editing. The recombinant 19-kDa C-terminus of PkMSP1P (PkMSP1P-19) was shown to bind specifically to human reticulocytes. However, immunoblotting data suggested that PkMSP1P-19-induced antibodies can recognize PkMSP1-19 and vice versa, confounding our ability to separate the properties of these two proteins. Targeted disruption of the pkmsp1p gene profoundly impacts parasite growth, demonstrating for the first time that PkMSP1P is important in in vitro growth of P. knowlesi and likely plays a distinct role from PkMSP1. Importantly, the MSP1P KO also enabled functional characterization of the PkMSP1P-19 antibodies, revealing clear immune cross-reactivity between the two paralogues, highlighting the vital importance of genetic studies in contextualizing recombinant protein studies. [ABSTRACT FROM AUTHOR]

Purpose: Lithotomy position has been widely used in the various urologic surgery. Occasionally sensory and motor problems of the lower extremities are occurred due to the lithotomy position and these deficits may be related with sciatic nerve injury (SNI). Inflammatory process is a factor to induce functional impairment after SNI. Therefore, we evaluated the role of adenosine A2A receptor agonists, polydeoxyribonucleotide (PDRN) showing anti-inflammatory effect on locomotor function following SNI in rats. Methods: Sciatic nerve was compressed with surgical clips for 1 minute after exposing of right sciatic nerve. After 3 days of SNI, PDRN (2, 4, and 8 mg/kg) was applied to the damaged area of sciatic nerve once daily for 10 days. Walking track analysis was conducted for locomotor function and plantar test was performed for thermal pain sensitivity. Level of cyclic adenosine- 3',5'-monophosphate (cAMP) were measured using enzyme-linked immunosorbent assay. Western blot analysis was performed for tumor necrosis factor (TNF)-a, interleukin (IL)-1ß, cAMP response element binding protein (CREP), vascular endothelial growth factor (VEGF). Immunofluorescence for neurofilament was also conducted. Results: Locomotor function was decreased and thermal pain sensitivity was increased by SNI. SNI enhanced proinflammatory cytokines' production, such as TNF-a and IL-1ß, while suppressed CREP phosphorylation and cAMP level. SNI also reduced the expression of VEGF and neurofilaments. However, treatment with PDRN inhibited proinflammatory cytokines' production and upregulated CREP phosphorylation and cAMP expression. PDRN also enhanced the expression of VEGF and neurofilaments. As a result, PDRN improved locomotor function and alleviated thermal hyperalgesia after SNI. Conclusions: PDRN has shown potential to be used as an effective treatment for neuropathic pain. [ABSTRACT FROM AUTHOR]