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Background Repairing large nerve defects remains challenging, and no definitive method has been established. We developed a nerve lengthening device for humans and achieved nerve defect repair through nerve lengthening in three cases. The purpose of this report is to describe the clinical course of three cases treated by nerve lengthening and to discuss its effectiveness in the treatment of nerve defects. Methods The target population included males and females aged 20–65 years with peripheral nerve injuries that cannot undergo primary suturing in the limbs were recruited. Three patients were included in this study. The nerve gaps were 13 mm, 15 mm and 100 mm, respectively. We developed a special nerve lengthening device. Starting from postoperative day 1, nerve lengthening was initiated on the proximal and distal ends at a rate of 0.5–1 mm daily (0.25 mm x 2–4 times) using the device. Monthly evaluations post-nerve suturing assessed nerve regeneration, pain, and adverse events. We observed postoperative courses for over 2 years. Results There were two radial nerve injury cases and one median nerve injury case. Functional recovery was observed in cases of shorter nerve defects repaired through nerve lengthening. However, significant functional restoration was not attainable for cases of longer nerve defects or those with prolonged post-injury intervals. Furthermore, in chronic cases, it was confirmed that this method could be used to gradually lengthened and repair severed nerves. There were no reports of pain or lengthening-related troubles during nerve lengthening. Conclusion It was found that good nerve regeneration can be achieved with short nerve defects. Compared to free nerve grafting, this new treatment is promising as it does not require the sacrifice of healthy nerves from the donor site or leave surgical scars. We demonstrated the potential of nerve lengthening as a new treatment option for nerve defects. This study is registered and published in the Japan Registry of Clinical Trials (Project No. jRCTs032180098, https://jrct.niph.go.jp/re/reports/detail/17847 ). Registration date: 28/01/2019.

Tissue engineering is an emerging field that has the potential to revolutionize the field of reconstructive surgery by providing off-the-shelf replacement products. The literature has become replete with tissue engineering studies, and the aim of this article is to review the contemporary application of tissue-engineered products. The use of tissue-engineered cartilage, bone and nerve in head and neck reconstruction is discussed.

Quantification of disease-associated proteins in the cerebrospinal fluid (CSF) has been critical for the study and treatment of several neurodegenerative disorders; however, mutant huntingtin protein (mHTT), the cause of Huntington's disease (HD), is at very low levels in CSF and, to our knowledge, has never been measured previously. We developed an ultrasensitive single-molecule counting (SMC) mHTT immunoassay that was used to quantify mHTT levels in CSF samples from individuals bearing the HD mutation and from control individuals in 2 independent cohorts. This SMC mHTT immunoassay demonstrated high specificity for mHTT, high sensitivity with a femtomolar detection threshold, and a broad dynamic range. Analysis of the CSF samples showed that mHTT was undetectable in CSF from all controls but quantifiable in nearly all mutation carriers. The mHTT concentration in CSF was approximately 3-fold higher in patients with manifest HD than in premanifest mutation carriers. Moreover, mHTT levels increased as the disease progressed and were associated with 5-year onset probability. The mHTT concentration independently predicted cognitive and motor dysfunction. Furthermore, the level of mHTT was associated with the concentrations of tau and neurofilament light chain in the CSF, suggesting a neuronal origin for the detected mHTT. We have demonstrated that mHTT can be quantified in CSF from HD patients using the described SMC mHTT immunoassay. Moreover, the level of mHTT detected is associated with proximity to disease onset and diminished cognitive and motor function. The ability to quantify CSF mHTT will facilitate the study of HD, and mHTT quantification could potentially serve as a biomarker for the development and testing of experimental mHTT-lowering therapies for HD. Not applicable. CHDI Foundation Inc.; Medical Research Council (MRC) UK; National Institutes for Health Research (NIHR); Rosetrees Trust; Swedish Research Council; and Knut and Alice Wallenberg Foundation.

In source localization of electroencephalograpic (EEG) signals, as well as in targeted transcranial electric current stimulation (tES), a volume conductor model is required to describe the flow of electric currents in the head. Boundary element models (BEM) can be readily computed to represent major tissue compartments, but cannot encode detailed anatomical information within compartments. Finite element models (FEM) can capture more tissue types and intricate anatomical structures, but with the higher precision also comes the need for semi-automated segmentation, and a higher computational cost. In either case, adjusting to the individual human anatomy requires costly magnetic resonance imaging (MRI), and thus head modeling is often based on the anatomy of an ‘arbitrary’ individual (e.g. Colin27). Additionally, existing reference models for the human head often do not include the cerebro-spinal fluid (CSF), and their field of view excludes portions of the head and neck—two factors that demonstrably affect current-flow patterns. Here we present a highly detailed FEM, which we call ICBM-NY, or \"New York Head\". It is based on the ICBM152 anatomical template (a non-linear average of the MRI of 152 adult human brains) defined in MNI coordinates, for which we extended the field of view to the neck and performed a detailed segmentation of six tissue types (scalp, skull, CSF, gray matter, white matter, air cavities) at 0.5mm3 resolution. The model was solved for 231 electrode locations. To evaluate its performance, additional FEMs and BEMs were constructed for four individual subjects. Each of the four individual FEMs (regarded as the ‘ground truth’) is compared to its BEM counterpart, the ICBM-NY, a BEM of the ICBM anatomy, an ‘individualized’ BEM of the ICBM anatomy warped to the individual head surface, and FEMs of the other individuals. Performance is measured in terms of EEG source localization and tES targeting errors. Results show that the ICBM-NY outperforms FEMs of mismatched individual anatomies as well as the BEM of the ICBM anatomy according to both criteria. We therefore propose the New York Head as a new standard head model to be used in future EEG and tES studies whenever an individual MRI is not available. We release all model data online at neuralengr.com/nyhead/ to facilitate broad adoption. •Individual head models for EEG source imaging and tCS stimulation are computationally expensive.•Instead, we propose a highly detailed standardized FEM model of the ICBM152 non-linear average head defined on MNI coordinates.•We approximate 4 individual heads and measure localization and targeting errors.•Our model compares favorably to individual and individualized models.•All data are made available.

RNA-binding proteins (RBP) are important regulators of RNA metabolism. In neurodegenerative disorders such as Huntington's Disease (HD), disrupted RBP-RNA interactions contribute to neuronal dysfunction. One such RBP, Midline 1 (MID1), has been shown to aberrantly associate with mutant huntingtin (Htt) RNA, enhancing its translation, yet the mechanism driving this effect remains unknown. Here, we develop a computational model to understand the role of MID1. Based on previously published data, our model predicts that MID1 increases the stability of the Htt RNA. We experimentally validate this prediction, showing that overexpression of MID1 significantly prolongs the half-life of mutant Htt RNA. Furthermore, we evaluate model refinements, including clustering of MID1-bound RNA, which allow capturing all key observations in the data. Together, we provide a data-driven framework that underlines the importance of RBP-RNA interaction in post-transcriptional regulation. This framework also shows how individual molecular reactions jointly determine RNA stability and protein levels in HD.

Earlier studies have shown sonographic enlargement of the ulnar nerve in patients with Hansen's neuropathy. The present study was performed to determine whether sonography or electrophysiological studies can detect the specific site of ulnar nerve pathology in leprosy. Eighteen patients (thirty arms) with Hansen's disease and an ulnar neuropathy of whom 66% had borderline tuberculoid (BT), 27% lepromatous leprosy (LL) and 7% mid-borderline (BB) leprosy were included in the study. Cross-sectional area (CSA) of ulnar nerve was measured every two centimeters from wrist to medial epicondyle and from there to axilla. All patients underwent standard motor and sensory nerve conduction studies of the ulnar nerve. Thirty age and sex matched controls underwent similar ulnar nerve CSA measurements and conduction studies. Ulnar nerve was clinically palpable in 19 of the 30 arms of patients. Motor and sensory nerve conduction studies of the ulnar nerve showed a reduced compound motor action potential and sensory nerve action potential amplitude in all patients. Motor Conduction Velocity (MCV) in patients were slower in comparison to controls, especially at the elbow and upper arm, but unable to exactly locate the site of the lesion. In comparison to controls the ulnar nerveCSA was larger in the whole arm in patients and quite specific the maximum enlargement was seen between nulnar sulcus and axilla, peaking at four centimeters above the sulcus. A unique sonographic pattern of nerve enlargement is noted in patients with ulnar neuropathy due to Hansen's disease, while this was not the case for the technique used until now, the electrodiagnostic testing. The enlargement starts at ulnar sulcus and is maximum four centimeters above the medial epicondyle and starts reducing further along the tract. This characteristic finding can help especially in diagnosing pure neuritic type of Hansen's disease, in which skin lesions are absent, and alsoto differentiate leprosy from other neuropathies in which nerve enlargement can occur.

Background Recent data suggest disparities in receipt of regional anesthesia prior to breast reconstruction. We aimed to understand factors associated with block receipt for mastectomy with immediate tissue expander (TE) reconstruction in a high-volume ambulatory surgery practice with standardized regional anesthesia pathways. Patients and Methods Patients who underwent mastectomy with immediate TE reconstruction from 2017 to 2022 were included. All patients were considered eligible for and were offered preoperative nerve blocks as part of routine anesthesia care. Interpreters were used for non-English speaking patients. Patients who declined a block were compared with those who opted for the procedure. Results Of 4213 patients who underwent mastectomy with immediate TE reconstruction, 91% accepted and 9% declined a nerve block. On univariate analyses, patients with the lowest rate of block refusal were white, non-Hispanic, English speakers, patients with commercial insurance, and patients undergoing bilateral reconstruction. The rate of block refusal went down from 12 in 2017 to 6% in 2022. Multivariable logistic regression demonstrated that older age ( p = 0.011), Hispanic ethnicity (versus non-Hispanic; p = 0.049), Medicaid status (versus commercial insurance; p < 0.001), unilateral surgery (versus bilateral; p = 0.045), and reconstruction in earlier study years (versus 2022; 2017, p < 0.001; 2018, p < 0.001; 2019, p = 0.001; 2020, p = 0.006) were associated with block refusal. Conclusions An established preoperative regional anesthesia program with blocks offered to all patients undergoing mastectomy with TE reconstruction can result in decreased racial disparities. However, continued differences in age, ethnicity, and insurance status justify future efforts to enhance preoperative educational efforts that address patient hesitancies in these subpopulations.

Nerve signal conduction, and particularly in myelinated nerve fibers, is a highly dynamic phenomenon that is affected by various biological and physical factors. The propagation of such moving electric signals may seemingly help elucidate the mechanisms underlying normal and abnormal functioning. This work aims to derive the exact physical wave solutions of the nonlinear partial differential equations with fractional beta-derivatives for the cases of transmission of nerve impulses in coupled nerves. To this end, the research uses a polynomial expansion approach to convert the problems of modeling nerve impulses into a second order elliptic nonlinear ordinary differential equation containing fractional beta-derivatives. Such transformation permits the study of solitary waves and their perturbation responses in the case of nerve fibers. The other direction of this study is applying the fixed-point theory to analyze the system dynamics and obtaining the Jacobian matrix to peruse the stability. Modulation instability regions are visualized, and nerve impulse waveforms are shown in three and two dimensions. The investigation depicts how impulse transmission amplitude and velocity are influenced by changing nerve fiber diameter and varying order physiological parameters. Soliton-like kink, anti-kink, and rogue wave solutions are revealed to explain nerve impulse propagation thoroughly. The analysis provides significant regions of equilibrium and modulational instability showing that the behavior of the nerve fibers is more dynamic than appreciated by most authors. Additionally, the authors suggest a refined mathematical formulation of the nerve impulse conduction with particular emphasis on the effect of fractional beta-derivatives on the transmission of waves. The obtained solutions and the graphs support their usefulness in various medical and biological industries, specifically the research on myelinated nerve fibers. The findings provide additional insights into the processes of nerve conduction which may be useful in the treatment of various diseases of the nervous system.

The locus for familial cortical myoclonic tremor with epilepsy (FCMTE) has long been mapped to 8q24 in linkage studies, but the causative mutations remain unclear. Recently, expansions of intronic TTTCA and TTTTA repeat motifs within were found to be involved in the pathogenesis of FCMTE in Japanese pedigrees. We aim to identify the causative mutations of FCMTE in Chinese pedigrees. We performed genetic linkage analysis by microsatellite markers in a five-generation Chinese pedigree with 55 members. We also used array-comparative genomic hybridisation (CGH) and next-generation sequencing (NGS) technologies (whole-exome sequencing, capture region deep sequencing and whole-genome sequencing) to identify the causative mutations in the disease locus. Recently, we used low-coverage (~10×) long-read genome sequencing (LRS) on the PacBio Sequel and Oxford Nanopore platforms to identify the causative mutations, and used repeat-primed PCR for validation of the repeat expansions. Linkage analysis mapped the disease locus to 8q23.3-24.23. Array-CGH and NGS failed to identify causative mutations in this locus. LRS identified the intronic TTTCA and TTTTA repeat expansions in as the causative mutations, thus corroborating the recently published results in Japanese pedigrees. We identified the pentanucleotide repeat expansion in as the causative mutation in Chinese FCMTE pedigrees. Our study also suggested that LRS is an effective tool for molecular diagnosis of genetic disorders, especially for neurological diseases that cannot be positively diagnosed by conventional clinical microarray and NGS technologies.

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.