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Introduction: The phrase "think globally, act locally", which has often been used to refer to conservation of the environment, highlights the importance of maintaining a holistic perspective and stipulates that each individual has a role to play in their community and larger world. Although peripheral nerve surgery has been largely unemphasized in global neurosurgical efforts, a wide disparity in peripheral nerve surgery is presumed to exist between high-income and low- and middle-income countries. Serbia is an upper middle-income country with a long history of peripheral nerve surgery., Research Question: How can understanding the development of peripheral nerve surgery in Serbia advance global education and improve peripheral nerve surgery worldwide?, Material and Methods: An anecdotal and narrative review of recent advances in peripheral nerve surgery in Serbia was conducted. The World Federation of Neurosurgical Society (WFNS) Peripheral Nerve Surgery Committee discussions on improving peripheral nerve surgery education were summarized., Results: In this manuscript, we describe the application of "think globally, act locally" to peripheral nerve surgery by providing an account of the development of peripheral nerve surgery in Serbia. Then, we report measures taken by the WFNS Peripheral Nerve Surgery Committee to improve education on peripheral nerve surgery in LMICs., Discussion and Conclusion: Viewing the development of peripheral nerve surgery in Serbia through the lens of "think globally, act locally" may guide the development of peripheral nerve surgery in LMICs., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Background: Although numerous articles have been published not only on the classification of thoracic outlet syndrome (TOS) but also on diagnostic standards, timing, and type of surgical intervention, there still remains some controversy because of the lack of level 1 evidence. So far, attempts to generate uniform reporting standards have not yielded conclusive results., Objective: To systematically review the body of evidence and reach a consensus among neurosurgeons experienced in TOS regarding anatomy, diagnosis, and classification., Methods: A systematic literature search on PubMed/MEDLINE was performed on February 13, 2021, yielding 2853 results. Abstracts were screened and classified. Recommendations were developed in a meeting held online on February 10, 2021, and refined according to the Delphi consensus method., Results: Six randomized controlled trials (on surgical, conservative, and injection therapies), 4 "guideline" articles (on imaging and reporting standards), 5 observational studies (on diagnostics, hierarchic designs of physiotherapy vs surgery, and quality of life outcomes), and 6 meta-analyses were identified. The European Association of Neurosurgical Societies' section of peripheral nerve surgery established 18 statements regarding anatomy, diagnosis, and classification of TOS with agreement levels of 98.4 % (±3.0)., Conclusion: Because of the lack of level 1 evidence, consensus statements on anatomy, diagnosis, and classification of TOS from experts of the section of peripheral nerve surgery of the European Association of Neurosurgical Societies were developed with the Delphi method. Further work on reporting standards, prospective data collections, therapy, and long-term outcome is necessary., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Objective:  Intraneural perineurioma is a rare tumor entity. It is a benign, very slow growing peripheral nerve sheath tumor that typically occurs in children and young adults. Motor deficits and muscle atrophy are classic presenting symptoms, while sensory deficits are rare at the onset of the disease. Recommended treatment strategies are lacking. We have evaluated the clinical follow-up and our experience with treatment of this rare entity., Methods:  A total of 30 patients with intraneural perineuriomas were assessed retrospectively. Demographic data, clinical symptoms, diagnostic examinations, therapy strategies, and clinical outcome were analyzed. Descriptive statistical methods were used for evaluation., Results:  The mean age was 22 years. Eleven women and 19 men were affected. The lesion occurred in the area of the upper extremity in 16 patients and in the area of the lower extremity in 14 patients. The most frequently affected nerve was the sciatic nerve, followed by the radial nerve. All patients showed a motor deficit to some extent. Seventy percent ( n  = 21) revealed atrophy, 43.3% ( n  = 13) had sensitive deficits, and 17% ( n  = 5) suffered of pain. Fascicle biopsies were performed in 26 patients (87%). In four patients (13%), the tumor was completely resected and then reconstructed via nerve grafts. Seventy percent of the patients ( n  = 21) received a magnetic resonance imaging (MRI) within 5 years postoperatively, in which no progress was shown., Conclusions:  To diagnose perineurioma, it is essential to take a biopsy of an enlarged, nonfunctional fascicle. Furthermore, a long-distance epineuriotomy to decompress the hypertrophic fascicle is reasonable. To preserve the nerves' residual function, a complete resection is not recommended. Results after grafting are poor. One reason for this might be residual tumor cells along the nerve that cannot be visualized. Malignant transformation is not yet reported and tumor growth is stable for years., Competing Interests: None declared., (Thieme. All rights reserved.)

High-resolution neurosonography (HRNS) has become a major imaging modality in assessment of peripheral nerve trauma in the recent years. However, the vascular changes of traumatic lesions have not been quantitatively assessed in HRNS. Here, we describe the vascular-ratio, a novel HRNS-based quantitative parameter for the assessment of intraneural vascular alterations in patients with nerve lesions. N = 9 patients suffering from peripheral nerve trauma were examined clinically, electrophysiologically and with HRNS (SonoSite Exporte, Fuji). Image analyses using Fiji included determination of the established fascicular ratio (FR), the cross-section ratio (CSR), and as an extension, the calculation of a vascular ratio (VR) of the healthy versus damaged nerve and a muscle perfusion ratio (MPR) in comparison to a healthy control group. The mean VR in the healthy part of the affected nerve (14.14%) differed significantly (p < 0.0001) from the damaged part (VR of 43.26%). This coincides with significant differences in the FR and CSR calculated for the damaged part versus the healthy part and the controls. In comparison, there was no difference between VRs determined for the healthy part of the affected nerve and the healthy controls (14.14% / 17.72%). However, the MPR of denervated muscles was significantly decreased compared to the non-affected contralateral controls. VR and MPR serve as additional tools in assessing peripheral nerve trauma. Image analysis and calculation are feasible. Combined with the more morphologic FR and CSR, the VR and MPR provide a more detailed insight into alterations accompanying nerve trauma.

Endothelial cells (ECs) have gained an increased scientific focus since they were reported to provide guidance for Schwann cells and subsequently following axons after nerve injuries. However, previous protocols for the isolation of nerve-derived ECs from human nerves are ineffective regarding time and yield. Therefore, we established a novel and efficient protocol for the isolation of ECs from human peripheral nerves by means of immunomagnetic CD31-antibody conjugated Dynabeads and assessed the purity of the isolated cells. The easy-to-follow and time-effective isolation method allows the isolation of > 95% pure ECs. The isolated ECs were shown to express highly specific EC marker proteins and revealed functional properties by formation of CD31 and VE-cadherin positive adherens junctions, as well as ZO-1 positive tight-junctions. Moreover, the formation of capillary EC-tubes was observed in-vitro. The novel protocol for the isolation of human nerve-derived ECs allows and simplifies the usage of ECs in research of the human blood-nerve-barrier and peripheral nerve regeneration. Additionally, a potential experimental application of patient-derived nerve ECs in the in-vitro vascularization of artificial nerve grafts is feasible.

Background: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals face considerable health disparities, often due to a lack of LGBTQ-competent care. Such disparities and lack of access to informed care are even more staggering in rural settings. As the state medical school for the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region, the University of Washington School of Medicine (UWSOM) is in a unique position to train future physicians to provide healthcare that meets the needs of LGBTQ patients both regionally and nationally., Objective: To describe our methodology of developing a student-driven longitudinal, region-wide curriculum to train medical students to provide high-quality care to LGBTQ patients., Methods: A 4-year LGBTQ Health Pathway was developed and implemented as a student-led initiative at the UWSOM. First- and second-year medical students at sites across the WWAMI region are eligible to apply. Accepted Pathway students complete a diverse set of pre-clinical and clinical components: online modules, didactic courses, longitudinal community service/advocacy work, a scholarly project, and a novel clinical clerkship in LGBTQ health developed specifically for this Pathway experience. Students who complete all requirements receive a certification of Pathway completion. This is incorporated into the Medical Student Performance Evaluation as part of residency applications., Results: The LGBTQ Health Pathway is currently in its fourth year. A total of 43 total students have enrolled, of whom 37.3% are based in the WWAMI region outside of Seattle. Pathway students have completed a variety of scholarly projects on LGBTQ topics, and over 1000 hours of community service/advocacy. The first cohort of 8 students graduated with a certificate of Pathway completion in spring 2020., Conclusions: The LGBTQ Health Pathway at UWSOM is a novel education program for motivated medical students across the 5-state WWAMI region. The diverse milestones, longitudinal nature of the program, focus on rural communities, and opportunities for student leadership are all strengths and unique aspects of this program. The Pathway curriculum and methodology described here serve as a model for student involvement and leadership in medical education. This program enables medical students to enhance their training in the care of LGBTQ patients and provides a unique educational opportunity for future physicians who strive to better serve LGBTQ populations., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Surgical treatment of retroperitoneal nerve and nerve-associated tumors is challenging, especially in cases with large extent. A single surgical access may have limitations and jeopardize patients., Objective: To present a series of patients to illustrate our individually tailored treatment concept and decision pathway., Methods: Retrospectively, clinical findings and imaging were related to surgical features and outcome. An algorithm for choice of approach was established., Results: From 2012 to 2017, we operated on n = 13 patients with retroperitoneal tumors, of these n = 9 were included (n = 6 female, n = 3 male). Histological findings included n = 2 schwannomas, n = 2 malignant peripheral nerve sheath tumors, n = 1 non-origin sarcoma, n = 1 perineurioma, n = 1 intraneural ganglion cyst, n = 1 lymphoma, and n = 1 paraganglioma. In n = 6 patients, we used a monoportal (retroperitoneal/transperitoneal) approach; in n = 2 patients, a biportal retroperitoneal to inguinal/transperitoneal to dorsal approach; and in n = 1 patient, a triportal transperitoneal to dorsal to gluteal approach. In n = 2 patients, we performed an open biopsy only; in n = 2 patients, a tumor enucleation; in n = 3 patients, a subtotal function-sparing resection; in n = 1 patient, a complete resection; and in n = 1 patient, intraneural decompression. In n = 1 patient, a new motor deficit appeared. n = 4 patients required further radio-oncological treatment. n = 8/9 patients are alive without tumor progress or recurrence., Conclusion: Retroperitoneal nerve or nerve-associated tumors encompass multiple entities. Depending on suspected histology and tumor extension, extensile or combined surgical approaches may be necessary. We present our algorithm for assessment and decision-making regarding surgical access ports and pathways., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Clinical and electrophysiological assessments prevail in evaluation of traumatic nerve lesions and their regeneration following nerve surgery in humans. Recently, high-resolution neurosonography (HRNS) and magnetic resonance neurography have gained significant importance in peripheral nerve imaging. The use of the grey-scale-based "fascicular ratio" (FR) was established using both modalities allowing for quantitative assessment., Objective: To find out whether FR using HRNS can assess nerve trauma and structural reorganization in correlation to postoperative clinical development., Methods: Retrospectively, 16 patients with operated traumatic peripheral nerve lesions were included. The control group consisted of 6 healthy volunteers. All imaging was performed with a 15 to 6 MHz ultrasound probe (SonoSite X-Porte; Fujifilm, Tokyo, Japan). FR was calculated using Fiji () on 8-bit-images ("MaxEntropy" using "Auto-Threshold" plug-in)., Results: Thirteen of 16 patients required autologous nerve grafting and 3 of 16 extra-intraneural neurolysis. There was no statistical difference between the FR of nonaffected patients' nerve portion with 43.48% and controls with FR 48.12%. The neuromatous nerve portion in grafted patients differed significantly with 85.05%. Postoperatively, FR values returned to normal with a mean of 39.33%. In the neurolyzed patients, FR in the affected portion was 78.54%. After neurolysis, FR returned to healthy values (50.79%). Ten of 16 patients showed clinical reinnervation., Conclusion: To our best knowledge, this is the first description of FR using HRNS for quantitative assessment of nerve damage and postoperative structural reorganization. Our results show a significant difference in healthy vs lesioned nerves and a change in recovering nerve portions towards a more "physiological" ratio. Further evaluation in larger patient groups is required., (Copyright © 2018 by the Congress of Neurological Surgeons.)

Chitosan is object of pharmaceutical research as a candidate permeability enhancer. However, chitosan was recently shown to reduce the oral bioavailability of acyclovir in humans. The effect of chitosan on two processes determining the oral bioavailability of acyclovir, bioaccessibility and intestinal absorption, was now investigated. Acyclovir's bioaccessibility was studied using the dynamic TNO gastro-Intestinal Model (TIM-1). Four epithelial models were used for permeability experiments: a Caco-2 cell model in absence and presence of mucus and both rat and porcine excised intestinal segments. Study concentrations of acyclovir (0.8 g/l) and chitosan (1.6 g/l and 4 g/l) were in line with those used in the aforementioned human study. No effect of chitosan was measured on the bioaccessibility of acyclovir in the TIM-1 system. The results obtained with the Caco-2 models were not in line with the in vivo data. The tissue segment models (rat and porcine intestine) showed a negative trend of acyclovir's permeation in presence of chitosan. The Ussing type chamber showed to be the most biopredictive, as it did point to an overall statistically significantly reduced absorption of acyclovir. This model thus seems most appropriate for pharmaceutical development purposes, in particular when interactions between excipients and drugs are to become addressed., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Vagus nerve stimulation (VNS) is an approved neurostimulation therapy. The purpose of the method is to treat patients with therapy-resistant depression (TRD). VNS exhibits antidepressive and stabilizing effects. This method is particularly useful as a long-term treatment, in which up to two-thirds of patients respond. The vagus nerve stimulator is positioned on the left vagus nerve during a surgical procedure and is activated telemetrically by a wand connected to a handheld computerized device. The treating physician can perform various adjustments of the vagus nerve stimulator during in-office visits (e.g., by modifying stimulation intensity or stimulation frequency) to achieve maximum therapeutic effects with low side effects. Set-up of the device usually takes several months. Typical side effects include wound infection, temporary salivation, coughing, paralysis of the vocal cords, bradycardia, or even asystole. The patient can stop the VNS by placing a magnet over the generator. The current protocol describes delivery of the specific stimulation tool and methods for adjusting the tuning parameters to achieve the best remission rates in patients with TRD.

Background: The predictors of shunt dependency such as amount of subarachnoid blood, acute hydrocephalus (HC), mode of aneurysm repair, clinical grade at admission and cerebro spinal fluid (CSF) drainage in excess of 1500 ml during the 1st week after the subarachnoid hemorrhage (SAH) have been identified as predictors of shunt dependency. Therefore our main objective is to identify predictors of CSF shunt dependency following non-traumatic subarachnoid hemorrhage., Methods: We performed a retrospective study including patients from January 1st 2012 to September 30th 2014 between 16 and 89 years old and had a non-traumatic subarachnoid hemorrhage in cranial computed tomography (CCT). We excluded patients with the following characteristics: Patients who died 3 days after admittance, lesions in brainstem, previous surgical treatment in another clinic, traumatic brain injury, pregnancy and disability prior to SAH.We performed a descriptive and comparative analysis as well as a logistic regression with the variables that showed a significant difference ( p  < 0.05). Hence we identified the variables concerning HC after non traumatic SAH and its correlation., Results: One hundred and seven clinical files of patients with non-traumatic SAH were analyzed. Twenty one (48%) later underwent shunt treatment. Shunt patients had significantly clinical and corroborated with doppler ultrasonography vasospasmus ( p  = 0.015), OR = 5.2. The amount of subarachnoidal blood according to modified Fisher grade was ( p  = 0.008) OR = 10.9. Endovascularly treated patients were less often shunted as compared with those undergoing surgical aneurysm repair ( p  = 0.004)., Conclusion: Vasospasmus and a large amount of ventricular blood seem to be a predictor concerning hydrocephalus after non-traumatic SAH. Hence according to our results the presence of these two variables could alert the treating physician in the decision whether an early shunt implantation < 7 days after SAH should be necessary., Competing Interests: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: We designed this study using super-selective intraoperative cervical nerve root stimulation aiming to support decision making about complete or partial contralateral C7 (cC7) nerve root transfer in patients with multiple cervical root avulsion injury., Methods: Super-selective intraoperative stimulations of anterior, lateral, medial and posterior aspect of C5-C8 nerve roots were performed. Compound muscle action potentials (CMAP) were recorded in the lateral part of the deltoid (DM), long head of biceps brachii (BCM), brachioradial (BRM), long head of triceps brachii (TCM), and extensor digitorum communis (EDC) muscle. Muscle strength was documented immediately after cC7 transfer procedures and on scheduled follow-up visits according to the Medical Research Council (MRC) scale., Results: In the DM, stimulation of the posterior aspect of C5 resulted in the largest CMAP amplitudes (2.0 mV ± 1.9; 80% ± 28.3). The BCM CMAPs induced by the different aspects of C6 all revealed homogenous stimulation results. Stimulation of the lateral aspect of C7 induced the largest amplitude of TCM CMAPs (1.3 mV ± 1.0; 67.1% ± 43.3). CMAP amplitudes of individual muscles and individual contributions of cervical nerve roots to the TCM varied between subjects. Overall donor side morbidity was low, no permanent motor deficit occurred., Conclusion: A super-selective intraoperative cervical nerve root stimulation may help minimize donor side morbidity in transfer procedures. Individual differences of cervical nerve root innervation pattern need to be addressed in future electrophysiological studies., Significance: Our study outlines individual differences of cervical nerve root innervation pattern., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low "variant" subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which, combined with chemotherapy, strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Bacteria can arrest their own growth and proliferation upon nutrient depletion and under various stressful conditions to ensure their survival. However, the molecular mechanisms responsible for suppressing growth and arresting the cell cycle under such conditions remain incompletely understood. Here, we identify post-transcriptional mechanisms that help enforce a cell-cycle arrest in Caulobacter crescentus following nutrient limitation and during entry into stationary phase by limiting the accumulation of DnaA, the conserved replication initiator protein. DnaA is rapidly degraded by the Lon protease following nutrient limitation. However, the rate of DnaA degradation is not significantly altered by changes in nutrient availability. Instead, we demonstrate that decreased nutrient availability downregulates dnaA translation by a mechanism involving the 5' untranslated leader region of the dnaA transcript; Lon-dependent proteolysis of DnaA then outpaces synthesis, leading to the elimination of DnaA and the arrest of DNA replication. Our results demonstrate how regulated translation and constitutive degradation provide cells a means of precisely and rapidly modulating the concentration of key regulatory proteins in response to environmental inputs.

Ubiquitin fusion degradation (UFD) substrates are delivered at the proteasome by a handover mechanism involving the ubiquitin-selective chaperone Cdc48 and the ubiquitin shuttle factor Rad23. Here, we show that introduction of a 20 amino acid peptide extension not only rendered degradation independent of Cdc48, in line with the model that this chaperone is involved in early unfolding events of tightly folded substrates, but at the same time relieved the need for efficient polyubiquitylation and the ubiquitin shuttle factor Rad23. Removal of the ubiquitylation sites in the N-terminal UFD signal made the degradation of this substrate strictly dependent on the peptide extension and also on Cdc48 and, importantly the presence of a functional ubiquitylation machinery. This suggests that the extension in the absence of N-terminal ubiquitylation sites is not properly positioned to engage the unfoldase machinery of the proteasome. Thus the need for efficient ubiquitylation and Cdc48 in facilitating proteasomal degradation are tightly linked but can be bypassed in the context of UFD substrates by the introduction of an unstructured extension. Our data suggest that polyubiquitin-binding complexes acting upstream of the proteasome, rather than the proteasome itself, can be primary determinants for the level of ubiquitylation required for protein degradation.

This review summarizes the current knowledge on anatomy and physiology of the human gastrointestinal tract in comparison with that of common laboratory animals (dog, pig, rat and mouse) with emphasis on in vivo methods for testing and prediction of oral dosage form performance. A wide range of factors and methods are considered in addition, such as imaging methods, perfusion models, models for predicting segmental/regional absorption, in vitro in vivo correlations as well as models to investigate the effects of excipients and the role of food on drug absorption. One goal of the authors was to clearly identify the gaps in today's knowledge in order to stimulate further work on refining the existing in vivo models and demonstrate their usefulness in drug formulation and product performance testing., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Objectives: Our main objective was to evaluate whether serum hypocalcaemia on the third day [defined as < 2.1 mmol/l (8.5 mg/dl)] is a prognostic factor for early mortality after moderate and severe traumatic brain injury (TBI)., Methods: We developed an ambispective comparative case control study. We evaluated clinical profiles from included patients from January 2005 to July 2009 and we prospectively recruited additional patients from August 2009 to July 2011. Patients were between 1 and 89 years old and had a Glasgow Coma Scale of 3-12 points following TBI., Results: We calculated an Odds Ratio of 5.2 (Confidence Intervals 95%: 4.48 to 6.032) for hypocalcaemia on day three, which was associated with death. Retrospectively (January 2005 to July 2009) we compiled data from 81 patients. Prospectively (August 2009 to July 2011) we recruited 41 patients. The adjusted variables in the logistic regression final model were: serum calcium on day three (Odds Ratio 3.5, Confidence Intervals 95%: 1·12 to 13·61, P < 0·028) and anisocoria (Odds Ratio 8·24, Confidence Intervals 95%: 1·3 to 67·35, P < 0·019) obtaining an adjusted R2 of 0·22 (P < 0·005)., Discussion: The serum levels of calcium on day three could be useful for the prediction of mortality in patients with moderate and severe TBI.

Objective: This study sought to determine the impact of spontaneous subarachnoid hemorrhage (SAH) on health-related quality of life (HRQOL)., Methods: Data were taken retrospectively from 601 patients (219 male, 382 female) treated between 1998 and 2008. Questionnaires concerning HRQOL were circulated prospectively, and the responses from 253 patients (81 male, 172 female) were analyzed. The questionnaires comprised the standardized Short-Form 36 (SF-36) and Short-Form 12 (SF-12) Health Surveys, a number of nonstandardized questions, and visual analogue scales. Statistical analysis of the results was exploratory, using unifactorial ANOVA (Scheffe), multivariate analyses of variance., Results: The HRQOL is reduced considerably by SAH and remains so for a period of 10 years. Physical and emotional domains are primarily affected, but also cognitive functions, including memory and concentration in particular. Similarly, certain roles are affected that prove difficult to rehabilitate after acute care and cause serious debility in the long term. The Hunt and Hess Scale, Glasgow Outcome Scale, and seizures were found to have the greatest impact on HRQOL., Conclusions: Documentation of HRQOL after 6 to 12 months is useful because patients are often found to have a diminished HRQOL in the absence of a clear physical impairment. Because psychological, emotional, cognitive, and social functioning influence HRQOL in the long term, efforts at rehabilitation should focus in particular on improving such factors. Documentation of HRQOL is a useful, additive tool for consolidating and evaluating the outcome, and a treatment end point after SAH, respectively., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The ubiquitin receptors Rad23 and Dsk2 deliver polyubiquitylated substrates to the proteasome for destruction. The C-terminal ubiquitin-associated (UBA) domain of Rad23 functions as a cis-acting stabilization signal that protects this protein from proteasomal degradation. Here, we provide evidence that the C-terminal UBA domains guard ubiquitin receptors from destruction by preventing initiation of degradation at the proteasome. We show that introduction of unstructured polypeptides that are sufficiently long to function as initiation sites for degradation abrogates the protective effect of UBA domains. Vice versa, degradation of substrates that contain an unstructured extension can be attenuated by the introduction of C-terminal UBA domains. Our study gains insight into the molecular mechanism responsible for the protective effect of UBA domains and explains how ubiquitin receptors can shuttle substrates to the proteasome without themselves becoming subject to proteasomal degradation.

We show that the ubiquitin-associated domain (UBA) of human p62/sequestosome-1 (SQSTM1) can delay degradation of proteasome substrates in yeast. Taking advantage of naturally occurring mutant UBA domains that are linked to Paget's disease of bone (PDB), we found that three of the four mutant UBA domains tested in this study were able to inhibit proteasomal degradation, albeit not to the same extent as the wild-type domain. Interestingly, the stability measured as the fraction of folded protein, and not the ubiquitin binding properties, of the PDB-associated UBA domains correlated with their protective effects. These data suggest that the protective effect of UBA domains depends on their structural integrity rather than ubiquitin binding capabilities., (Copyright 2010 Federation of European Biochemical Societies. All rights reserved.)

Background: Accurate detection of Hepatitis B Surface Antigen (HBsAg) is an important aid in the diagnosis of patients infected with the hepatitis B virus (HBV). A multi-center study was conducted to characterize the performance of the HBsAg assay on the family of Access immunoassay systems from Beckman Coulter., Methods: The Access HBsAg assay was characterized in a multi-center study and compared to the Abbott AxSYM* and PRISM* HBsAg assays. The bioMérieux VIDAS* assay was used to resolve discrepant results. Reproducibility studies (intra-assay, inter-assay and inter-lot) were performed with pooled serum samples (negative sample, close to cut off, low, medium and high positive samples). Analytical sensitivity, subtype and genotype detection were studied with various commercial panels (SFTS panel, WHO 80/549, WHO 00/588, Teragenix HBV Genotype panel). A panel of recombinant HBsAg mutant proteins was tested to investigate reactivity towards genetic mutations. Clinical sensitivity was verified with seroconversion panels and samples from subjects with known HBV infection. Analytical specificity was studied with samples from patients with potential cross-reactive infections. Clinical specificity was validated among blood donors and a hospitalized population., Results: The imprecision was < 10%. Analytical sensitivity was < or = 0.1 ng/mL (SFTS panel), 0.020 PEI Units/mL (ad panel), 0.024 PEI Units/mL (ay panel), 0.092 IU/mL with WHO 80/549 and 0.056 IU/mL with WHO 00/588. All genotype samples and HBsAg mutants were reactive with the Access HBsAg assay. Seroconversion panels tested showed no significant difference with the reference method. Sensitivity for subjects with known HBV infection was 100%. No interference with potentially cross-reactive infections was observed after confirmatory testing. Specificity was 99.96% (100% after confirmatory testing) in a blood donor population and 99.5% (100% after confirmatory testing) in a hospitalized population. Excellent separation of positive and negative populations was observed., Conclusions: The Access HBsAg and HBsAg Confirmatory assays meet all clinical and analytical performance requirements of assays for the detection of HBsAg.

Objective: Little is known about patient satisfaction and disability after brachial plexus surgery. Would patients undergo the procedure again, if they knew the current result beforehand? How do they rate their result and their disability?, Methods: Of 319 plexus patients who had undergone surgery between 1995 and 2005, 199 received a 65-item questionnaire. Measurement instruments included a new plexus-specific outcome questionnaire (Ulm Questionnaire) with categories of satisfaction, functionality, pain, comorbidities, and work; and the disability of the arm, shoulder, and hand questionnaire (DASH; scale, 0-100)., Results: Of 99 returned questionnaires, 70 were returned in a useful form for evaluation. The results of patients with C5-C6 lesions (21 of 70) are as follows: 90% (19 of 21) would undergo surgery again, 95% (20 of 21) were satisfied with the result, and 86% (18 of 21) subjectively improved. The mean DASH score was 41 (standard deviation [SD], 24). The results of patients with C5-C7 lesions (6 of 70) are as follows: 50% (3 of 6) were satisfied and would undergo surgery again, and 67% (4 of 6) improved. The mean DASH score was 46 (SD, 13). The results of patients with C5-T1 lesions (43 of 70) are as follows: 67% (29 of 43) would undergo surgery again, 81% (35 of 42) were satisfied, and 74% (32 of 43) reported improvement. The mean DASH score was 58 (SD, 26). The overall mean DASH score was 52 (SD, 26). Pain since the injury was prevalent in 86% of patients (60 of 70), back pain in 53%, and depression/anxiety in 21%. Fifty-two percent of those who worked before their injury (27 of 53 patients) remained unemployed or incapacitated for work. Forty-five percent of previous workers (24 of 53) returned to their former occupation. Occupational retraining was successful for 70% of patients (16 of 23). The mean duration until return to work was 9 months overall and 5 months for those who returned to their previous occupation., Conclusion: Eighty-seven percent of patients were satisfied with the results and 83% would undergo the procedure again. Despite a high satisfaction rate, patients remained considerably disabled, and half of the previous workers did not return to work. Occupational retraining is effective.

A protein that exemplifies the intimate link between the ubiquitin/proteasome system (UPS) and DNA repair is the yeast nucleotide excision repair (NER) protein Rad23 and its human orthologs hHR23A and hHR23B. Rad23, which was originally identified as an important factor involved in the recognition of DNA lesions, also plays a central role in targeting ubiquitylated proteins for proteasomal degradation, an activity that it shares with other ubiquitin receptors like Dsk2 and Ddi1. Although the finding that Rad23 serves as a ubiquitin receptor explains to a large extent its importance in proteasomal degradation, the precise mode of action of Rad23 in NER and the possible link with the UPS is less clear. In this review, we discuss our present knowledge on the functions of Rad23 in protein degradation and DNA repair and speculate on the importance of the dual roles of Rad23 for the cell's ability to cope with stress conditions.

Besides the carpal tunnel syndrome, the cubital tunnel syndrome (CuTS) represents the second most frequent nerve entrapment syndrome. The current gold standard for surgical therapy consists of simple open decompression. Recently, an endoscopic procedure involving long-distance decompression of the ulnar nerve has been developed and this is the topic of the present study. The first part of this paper describes preliminary anatomic investigations on 22 cadaver arms. In every sample we observed a thickening of the submuscular membrane between the heads of the flexor carpi ulnaris (FCU) which surrounds the ulnar nerve. This was especially the case for the first 10 cm from the medial epicondyle In the second part we report our experiences with this endoscopic decompression procedure in 36 patients. With this endoscopic decompression we achieved good to very good results according to the Bishop classification in 28 patients (78%). On the basis of anatomic considerations and our current experience, the endoscopic procedure seems to represent a promising alternative to simple decompression.

An erroneous transcriptional process, known as molecular misreading, gives rise to an alternative transcript of the ubiquitin B (UBB) gene. This transcript encodes the protein UBB(+1), which comprises a ubiquitin moiety and a 19-aa C-terminal extension. UBB(+1) is found in affected neurons in neurodegenerative diseases and behaves as an atypical ubiquitin fusion degradation (UFD) proteasome substrate that is poorly degraded and impedes the ubiquitin/proteasome system. Here, we show that the limited length of UBB(+1) is responsible for its inefficient degradation and inhibitory activity. Designed UFD substrates with an equally short 19-aa or a 20-aa C-terminal extension were also poorly degraded and had a general inhibitory activity on the ubiquitin/proteasome system in two unrelated cell lines. Extending the polypeptide to 25 aa sufficed to convert the protein into an efficiently degraded proteasome substrate that lacked inhibitory activity. A similar length dependency was found for degradation of two UFD substrates in Saccharomyces cerevisiae, which suggests that the mechanisms underlying this length constraint are highly conserved. Extending UBB(+1) also converted this protein into an efficient substrate of the proteasome. These observations provide an explanation for the accumulation of UBB(+1) in neurodegenerative disorders and offers new insights into the physical constraints determining proteasomal degradation.

Background: From 2005 through 2007, Seattle health care providers identified cases of primary multiclass drug-resistant (MDR) HIV-1 with common patterns of resistance to antiretrovirals (ARVs). Through surveillance activities and genetic analysis, the local Health Department and the University of Washington identified phylogenetically linked cases among ARV treatment-naive and -experienced individuals., Methods: HIV-1 pol nucleotide consensus sequences submitted to the University of Washington Clinical Virology Laboratory were assessed for phylogenetically related MDR HIV. Demographic and clinical data collected included HIV diagnosis date, ARV history, and laboratory results., Results: Seven ARV-naive men had phylogenetically linked MDR strains with resistance to most ARVs; these were linked to 2 ARV-experienced men. All 9 men reported methamphetamine use and multiple anonymous male partners. Primary transmissions were diagnosed for more than a 2-year period, 2005-2007. Three, including the 2 ARV-experienced men, were prescribed ARVs., Conclusions: This cluster of 9 men with phylogenetically related highly drug-resistant MDR HIV strains and common risk factors but without reported direct epidemiologic links may have important implications to public health. This cluster demonstrates the importance of primary resistance testing and of collaboration between the public and private medical community in identifying MDR outbreaks. Public health interventions and surveillance are needed to reduce transmission of MDR HIV-1.

In this article the authors attempt to raise awareness of the pitfalls and controversial issues in nerve tumor surgery. In a case-guided format, examples of ambiguous findings, inappropriate tumor removal, repeated surgery, and nerve repairs are provided. The authors also discuss the need to establish a correct diagnosis preoperatively and to avoid the erroneous identification of malignant peripheral nerve sheath tumors (MPNSTs). They emphasize that not all of the principles of soft tissue sarcoma treatment protocols are applicable to MPNST. A situation of repeated surgery for supposedly malignant tumor is described, and an outline of the indications for, and an approach to, repair after lesion removal is given.

In this study, we describe an in silico method to design peptides that can be made of non-natural amino acids and elicit specific membrane-interacting properties. The originality of the method holds in the capacities developed to design peptides from any non-natural amino acids as easily as from natural ones, and to test the structure stability by an angular dynamics rather than the currently-used molecular dynamics. The goal of this study was to design a non-natural tilted peptide. Tilted peptides are short protein fragments able to destabilize lipid membranes and characterized by an asymmetric distribution of hydrophobic residues along their helix structure axis. The method is based on the random generation of peptides and their selection on three main criteria: mean hydrophobicity and the presence of at least one polar residue; tilted insertion at the level of the acyl chains of lipids of a membrane; and conformational stability in that hydrophobic phase. From 10,000,000 randomly-generated peptides, four met all the criteria. One was synthesized and tested for its lipid-destabilizing properties. Biophysical assays showed that the "de novo" peptide made of non-natural amino acids is helical either in solution or into lipids as tested by Fourier transform infrared spectroscopy and is able to induce liposome fusion. These results are in agreement with the calculations and validate the theoretical approach.

An increased risk of colon cancer has been observed in individuals with long-standing ulcerative colitis (UC). In order to identify molecular genetic markers for the development of neoplasia in UC individuals, we isolated DNA from normal, regenerative, and dysplastic mucosa, as well as from colon carcinomas from UC patients, and evaluated it for the presence of mutations in microsatellite DNA sequences. DNAs isolated from regenerative mucosa displayed microsatellite mutation. These observations suggest that DNA mutation is an early event in the UC disease process.

Aberrant crypt foci (ACF) are distinct microscopic lesions of the colon thought to be the earliest identifiable precursors of colon cancer. As precursors of colon cancer, ACF may contain mutations in genes that are altered early in colorectal tumorigenesis. Candidates for these genes include APC, K-Ras, and those of the DNA mismatch repair system. Some colon cancers with mutations in DNA mismatch repair genes are characterized by genomic instability at simple repeated sequences, also known as microsatellite instability. In this study, we analyzed 19 ACF (> or = 20 crypts/focus) and adjoining, microscopically normal colonic mucosa from 10 colon cancer patients for the presence of microsatellite instability. DNA from two ACF from two different patients displayed microsatellite instability. None of the DNA samples from normal mucosa displayed microsatellite instability. These observations support the role of ACF as a precursor to colon cancer and provide some evidence that mutations in DNA mismatch repair genes are early somatic events in colon cancer.

Almost 20% of colon cancers are characterized by genomic instability at simple repeated sequences. This instability is the result of a deficient DNA mismatch repair system. Sporadic, as well as hereditary carcinomas of the proximal colon display this effect. In this study, we examined colorectal adenocarcinoma cell lines, with or without wild-type adenomatous polyposis coli (APC) protein, for the presence of microsatellite instability. The three cell lines that maintained full-length APC protein also displayed the highest level of instability, suggesting a negative correlation between APC mutations and microsatellite instability. This data, in addition to other studies that show a negative correlation between microsatellite instability and mutations in p53 and K-ras, support the idea of a second pathway for colorectal cancer development.