Broadband Tunable Infrared Light Emission from Metal-Oxide-Semiconductor Tunnel Junctions in Silicon Photonics.

Broadband near-infrared light emitting tunnel junctions are demonstrated with efficient coupling to a silicon photonic waveguide. The metal oxide semiconductor devices show long hybrid photonic-plasmonic mode propagation lengths of approximately 10 µm and thus can be integrated into an overcoupled resonant cavity with quality factor Q ≈ 49, allowing for tens of picowatt near-infrared light emission coupled directly into a waveguide. The electron inelastic tunneling transition rate and the cavity mode density are modeled, and the transverse magnetic (TM) hybrid mode excitation rate is derived. The results coincide well with polarization resolved experiments. Additionally, current-stressed devices are shown to emit unpolarized light due to radiative recombination inside the silicon electrode.

Diagnosis and management of urinary bladder paragangliomas: A Sino-American-European retrospective observational study.

OBJECTIVE: Paragangliomas of the urinary bladder (UBPGLs) are rare neuroendocrine tumours and pose a diagnostic and surgical challenge. It remains unclear what factors contribute to a timely presurgical diagnosis. The purpose of this study is to identify factors contributing to missing the diagnosis of UBPGLs before surgery. DESIGN, PATIENTS AND MEASUREMENTS: A total of 73 patients from 11 centres in China, and 51 patients from 6 centres in Europe and 1 center in the United States were included. Clinical, surgical and genetic data were collected and compared in patients diagnosed before versus after surgery. Logistic regression analysis was used to identify clinical factors associated with initiation of presurgical biochemical testing. RESULTS: Among all patients, only 47.6% were diagnosed before surgery. These patients were younger (34.0 vs. 54.0 years, p < .001), had larger tumours (2.9 vs. 1.8 cm, p < .001), and more had a SDHB pathogenic variant (54.7% vs. 11.9%, p < .001) than those diagnosed after surgery. Patients with presurgical diagnosis presented with more micturition spells (39.7% vs. 15.9%, p = .003), hypertension (50.0% vs. 31.7%, p = .041) and catecholamine-related symptoms (37.9% vs. 17.5%, p = .012). Multivariable logistic analysis revealed that presence of younger age (<35 years, odds ratio [OR] = 6.47, p = .013), micturition spells (OR = 6.79, p = .007), hypertension (OR = 3.98, p = .011), and sweating (OR = 41.72, p = .013) increased the probability of initiating presurgical biochemical testing. CONCLUSIONS: Most patients with UBPGL are diagnosed after surgery. Young age, hypertension, micturition spells and sweating are clues in assisting to initiate early biochemical testing and thus may establish a timely presurgical diagnosis.

Sex differences in cerebral blood flow among adolescents with bipolar disorder.

BACKGROUND: Abnormalities in cerebral blood flow (CBF) are common in bipolar disorder (BD). Despite known differences in CBF between healthy adolescent males and females, sex differences in CBF among adolescents with BD have never been studied. OBJECTIVE: To examine sex differences in CBF among adolescents with BD versus healthy controls (HC). METHODS: CBF images were acquired using arterial spin labeling (ASL) perfusion magnetic resonance imaging (MRI) in 123 adolescents (72 BD: 30M, 42F; 51 HC: 22M, 29F) matched for age (13-20 years). Whole brain voxel-wise analysis was performed in a general linear model with sex and diagnosis as fixed factors, sex-diagnosis interaction effect, and age as a covariate. We tested for main effects of sex, diagnosis, and their interaction. Results were thresholded at cluster forming p = 0.0125, with posthoc Bonferroni correction (p = 0.05/4 groups). RESULTS: A main effect of diagnosis (BD > HC) was observed in the superior longitudinal fasciculus (SLF), underlying the left precentral gyrus (F =10.24 (3), p < 0.0001). A main effect of sex (F > M) on CBF was detected in the precuneus/posterior cingulate cortex (PCC), left frontal and occipital poles, left thalamus, left SLF, and right inferior longitudinal fasciculus (ILF). No regions demonstrated a significant sex-by-diagnosis interaction. Exploratory pairwise testing in regions with a main effect of sex revealed greater CBF in females with BD versus HC in the precuneus/PCC (F = 7.1 (3), p < 0.01). CONCLUSION: Greater CBF in female adolescents with BD versus HC in the precuneus/PCC may reflect the role of this region in the neurobiological sex differences of adolescent-onset BD. Larger studies targeting underlying mechanisms, such as mitochondrial dysfunction or oxidative stress, are warranted.

A prospective case series to evaluate subcostal nerve injury with high-resolution ultrasound in posterior retroperitoneoscopic adrenalectomy.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy has several advantages over transabdominal laparoscopic adrenalectomy regarding operating time, blood loss, postoperative pain, and recovery. However, postoperatively several patients report chronic pain or hypoesthesia. We hypothesized that these symptoms may be the result of damage to the subcostal nerve, because it passes the surgical area. METHODS: A prospective single-center case series was performed in adult patients without preoperative pain or numbness of the abdominal wall who underwent unilateral posterior retroperitoneoscopic adrenalectomy. Patients received pre- and postoperative questionnaires and a high-resolution ultrasound scan of the subcostal nerve and abdominal wall muscles was performed before and directly after surgery. Clinical evaluation at 6 weeks was performed with repeat questionnaires, physical examination, and high-resolution ultrasound. Long-term recovery was evaluated with questionnaires, and photographs from the patients were examined for abdominal wall asymmetry. RESULTS: A total of 25 patients were included in the study. There were no surgical complications. Preoperative visualization of the subcostal nerve was possible in all patients. At 6 weeks, ultrasound showed nerve damage in 15 patients, with no significant association between nerve damage and postsurgical pain. However, there was a significant association between nerve damage and hypoesthesia (p = 0.01), sensory (p < 0.001), and motor (p < 0.001) dysfunction on physical examination. After a median follow-up of 18 months, 5 patients still experienced either numbness or muscle weakness, and one patient experienced chronic postsurgical pain. CONCLUSION: In this exporatory case series the incidence of postoperative damage to the subcostal nerve, both clinically and radiologically, was 60% after posterior retroperitoneoscopic adrenalectomy. There was no association with pain, and the spontaneous recovery rate was high.

Longitudinal cerebral perfusion in presymptomatic genetic frontotemporal dementia: GENFI results.

INTRODUCTION: Effective longitudinal biomarkers that track disease progression are needed to characterize the presymptomatic phase of genetic frontotemporal dementia (FTD). We investigate the utility of cerebral perfusion as one such biomarker in presymptomatic FTD mutation carriers. METHODS: We investigated longitudinal profiles of cerebral perfusion using arterial spin labeling magnetic resonance imaging in 42 C9orf72, 70 GRN, and 31 MAPT presymptomatic carriers and 158 non-carrier controls. Linear mixed effects models assessed perfusion up to 5 years after baseline assessment. RESULTS: Perfusion decline was evident in all three presymptomatic groups in global gray matter. Each group also featured its own regional pattern of hypoperfusion over time, with the left thalamus common to all groups. Frontal lobe regions featured lower perfusion in those who symptomatically converted versus asymptomatic carriers past their expected age of disease onset. DISCUSSION: Cerebral perfusion is a potential biomarker for assessing genetic FTD and its genetic subgroups prior to symptom onset. HIGHLIGHTS: Gray matter perfusion declines in at-risk genetic frontotemporal dementia (FTD). Regional perfusion decline differs between at-risk genetic FTD subgroups . Hypoperfusion in the left thalamus is common across all presymptomatic groups. Converters exhibit greater right frontal hypoperfusion than non-converters past their expected conversion date. Cerebral hypoperfusion is a potential early biomarker of genetic FTD.

Characterisation of an Adult Zebrafish Model for SDHB-Associated Phaeochromocytomas and Paragangliomas.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours arising from chromaffin cells. Pathogenic variants in the gene succinate dehydrogenase subunit B (SDHB) are associated with malignancy and poor prognosis. When metastases arise, limited treatment options are available. The pathomechanism of SDHB-associated PPGL remains largely unknown, and the lack of suitable models hinders therapy development. Germline heterozygous SDHB pathogenic variants predispose to developing PPGLs with a life-long penetrance of around 50%. To mimic the human disease phenotype, we characterised adult heterozygous sdhb mutant zebrafish as a potential model to study SDHB-related PPGLs. Adult sdhb mutant zebrafish did not develop an obvious tumour phenotype and were anatomically and histologically like their wild-type siblings. However, sdhb mutants showed significantly increased succinate levels, a major hallmark of SDHB-related PPGLs. While basal activity was increased during day periods in mutants, mitochondrial complex activity and catecholamine metabolite levels were not significantly different. In conclusion, we characterised an adult in vivo zebrafish model, genetically resembling human carriers. Adult heterozygous sdhb mutants mimicked their human counterparts, showing systemic elevation of succinate levels despite the absence of a tumour phenotype. This model forms a promising basis for developing a full tumour phenotype and gaining knowledge of the pathomechanism behind SDHB-related PPGLs.

Intraputamenal Cerebral Dopamine Neurotrophic Factor in Parkinson's Disease: A Randomized, Double-Blind, Multicenter Phase 1 Trial.

BACKGROUND: Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that protects dopamine neurons and improves motor function in animal models of Parkinson's disease (PD). OBJECTIVE: The primary objectives of this study were to assess the safety and tolerability of both CDNF and the drug delivery system (DDS) in patients with PD of moderate severity. METHODS: We assessed the safety and tolerability of monthly intraputamenal CDNF infusions in patients with PD using an investigational DDS, a bone-anchored transcutaneous port connected to four catheters. This phase 1 trial was divided into a placebo-controlled, double-blind, 6-month main study followed by an active-treatment 6-month extension. Eligible patients, aged 35 to 75 years, had moderate idiopathic PD for 5 to 15 years and Hoehn and Yahr score ≤ 3 (off state). Seventeen patients were randomized to placebo (n = 6), 0.4 mg CDNF (n = 6), or 1.2 mg CDNF (n = 5). The primary endpoints were safety and tolerability of CDNF and DDS and catheter implantation accuracy. Secondary endpoints were measures of PD symptoms, including Unified Parkinson's Disease Rating Scale, and DDS patency and port stability. Exploratory endpoints included motor symptom assessment (PKG, Global Kinetics Pty Ltd, Melbourne, Australia) and positron emission tomography using dopamine transporter radioligand [18 F]FE-PE2I. RESULTS: Drug-related adverse events were mild to moderate with no difference between placebo and treatment groups. No severe adverse events were associated with the drug, and device delivery accuracy met specification. The severe adverse events recorded were associated with the infusion procedure and did not reoccur after procedural modification. There were no significant changes between placebo and CDNF treatment groups in secondary endpoints between baseline and the end of the main and extension studies. CONCLUSIONS: Intraputamenally administered CDNF was safe and well tolerated, and possible signs of biological response to the drug were observed in individual patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Extensive Carbon Contribution of Inundated Terrestrial Plants to Zooplankton Biomass in a Eutrophic Lake.

Organic carbon derived from terrestrial plants contributes to aquatic consumers, e.g., zooplankton in lakes. The degree of the contribution depends on the availability of terrestrial organic carbon in lake organic pool and the transfer efficiency of the carbon. Terrestrial organic carbon is poor-quality food for zooplankton with a mismatch of nutrition content and was incorporated to zooplankton with much lower efficiency than phytoplankton. Contributions of terrestrial carbon to zooplankton generally decrease with an increase in phytoplankton production, indicating a preferential incorporation of phytoplankton in previous investigations. However, in eutrophic lakes, the dominating cyanobacteria were of poor quality and incorporated to consumers inefficiently too. In that case, zooplankton in eutrophic wetlands, where cyanobacteria dominate the phytoplankton production and massive terrestrial plants are inundated, may not preferentially incorporate poor food-quality phytoplankton resource to their biomass. Therefore, we hypothesize that carbon contributions of terrestrial vegetation to zooplankton and to lake particulate organic pool should be similar in such aquatic ecosystems. We tested this hypothesis by sampling zooplankton and carbon sources in Ming Lake (Jinan University Campus, southern China) which was overgrown by terrestrial plants after drying and re-flooded. After 60 days of observations at weekly (or biweekly) intervals, applying stable carbon (13C), nitrogen (15 N), and hydrogen (2H) isotopic analysis and a stable isotope mixing model, we estimated the occurrence of extensive carbon contribution (≥ 50%) of flooded terrestrial plants to cladocerans and copepods. Contribution of inundated terrestrial plants to cladocerans was similar to that to lake particulate organic pool. Thus, our study quantified the role of terrestrial carbon in eutrophic wetlands, enhancing our understanding of cross-ecosystem interactions in food webs with an emphasis on the resource quality.

Study of severe migraine in general medicine.

OBJECTIVE: To evaluate the criteria of severe migraine in a general population consulting a general practitioner (GP) and to evaluate assessment of migraine severity in the migraine patient as well as treating physicians' knowledge of their patient's migraine and its severity. METHODS: We questioned voluntary headache patients who had an appointment with a GP about the severity of their migraine using recognized scores - HIT-6 and MIDAS - as well as with a specific questionnaire created for the study. We compared the criteria for severe migraine with the patient's description of their symptoms, their HIT-6 score, their MIDAS score, and the GP's opinion, analyzing collected data using means and standard deviations. RESULTS: We found that 152 out of 942 headache patients questioned in the general medicine setting met the criteria of "strict migraine", corresponding to 10.3% prevalence. Seventy-one out of 100 patients (71%) with migraine who filled out in the questionnaire completely had what is characterized as "severe migraine". Forty-one (57%) of the 71 severe migraine patients presented the strict criteria. Additionally, 21 of the 29 (72%) patients with a non-severe diagnosis agreed that their headache was non-severe. When the HIT-6 score was stratified above 65, correspondence between the questionnaire-derived diagnosis and patient perception of severity was observed in 36 of the 58 (62%) with severe migraine. Finally, participating GPs were aware of their patient's migraine for 60% of patients with migraine. GPs correctly classified the severity of their patient's migraine for 55 (36%) patients. CONCLUSION: GP education and training about migraine remain a public health issue. The diagnosis of severe migraine is necessary for proper patient management. Current criteria for severe migraine are not robust enough; we propose a modification of the criteria.

The interaction of α-synuclein and Tau: A molecular conspiracy in neurodegeneration?

α-synuclein and Tau are proteins prone to pathological misfolding and aggregation that are normally found in the presynaptic and axonal compartments of neurons. Misfolding initiates a homo-oligomerization and aggregation cascade culminating in cerebral accumulation of aggregated α-synuclein and Tau in insoluble protein inclusions in multiple neurodegenerative diseases. Traditionally, α-synuclein-containing Lewy bodies have been associated with Parkinson's disease and Tau-containing neurofibrillary tangles with Alzheimer's disease and various frontotemporal dementia syndromes. However, there is significant overlap and co-occurrence of α-synuclein and Tau pathologies in a spectrum of neurodegenerative diseases. Importantly, α-synuclein and Tau can interact in cells, and their pathological conformations are capable of templating further misfolding and aggregation of each other. They also share a number of protein interactors indicating that network perturbations may contribute to chronic proteotoxic stress and neuronal dysfunction in synucleinopathies and tauopathies, some of which share similarities in both neuropathological and clinical manifestations. In this review, we focus on the protein interactions of these two pathologically important proteins and consider a network biology perspective towards neurodegenerative diseases.

Multidisciplinary integrated care pathway for von Hippel-Lindau disease.

BACKGROUND: Clinical pathways are care plans established to describe essential steps in the care of patients with a specific clinical problem. They translate (inter)national guidelines into local applicable protocols and clinical practice. The purpose of this article is to establish a multidisciplinary integrated care pathway for specialists and allied health care professionals in caring for individuals with von Hippel-Lindau (VHL) disease. METHODS: Using a modified Delphi consensus-making process, a multidisciplinary panel from 5 Dutch University Medical Centers produced an integrated care pathway relating to the provision of care for patients with VHL by medical specialists, specialized nurses, and associated health care professionals. Patient representatives cocreated the pathway and contributed quality criteria from the patients' perspective. RESULTS: The panel agreed on recommendations for the optimal quality of care for individuals with a VHL gene mutation. These items were the starting point for the development of a patient care pathway. With international medical guidelines addressing the different VHL-related disorders, this article presents a patient care pathway as a flowchart that can be incorporated into VHL expertise clinics or nonacademic treatment clinics. CONCLUSIONS: Medical specialists (internists, urologists, neurosurgeons, ophthalmologists, geneticists, medical oncologists, neurologists, gastroenterologists, pediatricians, and ear-nose-throat specialists) together with specialized nurses play a vital role alongside health care professionals in providing care to people affected by VHL and their families. This article presents a set of consensus recommendations, supported by organ-specific guidelines, for the roles of these practitioners in order to provide optimal VHL care. This care pathway can form the basis for the development of comprehensive, integrated pathways for multiple neoplasia syndromes.

Integrated control of coronary blood flow in exercising swine by adenosine, nitric oxide, and KATP channels.

The interplay of mechanisms regulating coronary blood flow (CBF) remains incompletely understood. Previous studies in dogs indicated that CBF regulation by KATP channels, adenosine, and nitric oxide (NO) follows a nonlinear redundancy design and fully accounted for exercise-induced coronary vasodilation. Conversely, in swine, these mechanisms appear to regulate CBF in a linear additive fashion with considerable exercise-induced vasodilation remaining when all three mechanisms are inhibited. A direct comparison between these studies is hampered by the different doses and administration routes (intravenous vs. intracoronary) of drugs inhibiting these mechanisms. Here, we investigated the role of KATP channels, adenosine, and NO in CBF regulation in swine using identical drug regimen as previously employed in dogs. Instrumented swine were exercised on a motor-driven treadmill, before and after blockade of KATP channels (glibenclamide, 50 µg/kg/min ic) and combination of inhibition of NO synthase (Nω-nitro-l-arginine, NLA, 1.5 mg/kg ic) and adenosine receptors (8-phenyltheophylline, 8PT, 5 mg/kg iv) or their combination NLA + 8PT + glibenclamide. Glibenclamide and NLA + 8PT each produced coronary vasoconstriction both at rest and during exercise, whereas the combination of NLA + 8PT + glibenclamide resulted in a small further coronary vasoconstriction compared with NLA + 8PT that was, however, less than the sum of the vasoconstriction produced by NLA + 8PT and glibenclamide, each. Thus, in contrast to previous observations in the dog, 1) the coronary vasoconstrictor effect of glibenclamide was not enhanced in the presence of NLA + 8PT and 2) the exercise-induced increase in CBF was largely maintained. These findings show profound species differences in the mechanisms controlling CBF at rest and during exercise.NEW & NOTEWORTHY The present study demonstrates important species differences in the regulation of coronary blood flow by adenosine, NO, and KATP channels at rest and during exercise. In swine, these mechanisms follow a linear additive design, as opposed to dogs which follow a nonlinear redundant design. Simultaneous blockade of all three mechanisms virtually abolished exercise-induced coronary vasodilation in dogs, whereas a substantial vasodilator reserve could still be recruited during exercise in swine.

Catecholamines Induce Trained Immunity in Monocytes In Vitro and In Vivo.

RATIONALE: Exposure to high catecholamine levels is associated with inflammatory changes of myeloid cells and atherosclerosis, but the underlying mechanisms are only partly understood. OBJECTIVE: To investigate whether the proinflammatory effects of noradrenaline and adrenaline can, in part, be explained by the induction of an immunologic memory in innate immune cells, termed trained immunity. METHODS AND RESULTS: In vitro, we exposed human primary monocytes to (nor)adrenaline for 24 hours, after which cells were rested and differentiated to macrophages over 5 days. After restimulation with lipopolysaccharide on day 6, (nor)adrenaline-exposed cells showed increased TNF-α (tumor necrosis factor-α) production. This coincided with an increase in glycolysis and oxidative phosphorylation measured with Seahorse technology on day 6 before restimulation. Inhibition of the ß-adrenoreceptor-cAMP signaling pathway prevented the induction of training. In vivo, we studied the functional, transcriptional, and epigenetic impact of peak-wise exposure to high catecholamine levels on monocytes isolated from pheochromocytoma/paraganglioma (PHEO) patients. In PHEO patients (n=10), the peripheral blood cell composition showed a myeloid bias and an increase of the inflammatory CD14++CD16+ (cluster of differentiation) intermediate monocyte subset compared with controls with essential hypertension (n=14). Ex vivo production of proinflammatory cytokines was higher in PHEO patients. These inflammatory changes persisted for 4 weeks after surgical removal of PHEO. Transcriptome analysis of circulating monocytes at baseline showed various differentially expressed genes in inflammatory pathways in PHEO patients; epigenetic profiling of the promoters of these genes suggests enrichment of the transcriptionally permissive chromatin mark H3K4me3 (trimethylation of lysine 4 on histone H3), indicative of in vivo training. CONCLUSIONS: Catecholamines induce long-lasting proinflammatory changes in monocytes in vitro and in vivo, indicating trained immunity. Our data contribute to the understanding of pathways driving inflammatory changes in conditions characterized by high catecholamine levels and propose that trained immunity underlies the increased cardiovascular event rate in PHEO patients.

[18F]FDG-PET/CT radiomics for the identification of genetic clusters in pheochromocytomas and paragangliomas.

OBJECTIVES: Based on germline and somatic mutation profiles, pheochromocytomas and paragangliomas (PPGLs) can be classified into different clusters. We investigated the use of [18F]FDG-PET/CT radiomics, SUVmax and biochemical profile for the identification of the genetic clusters of PPGLs. METHODS: In this single-centre cohort, 40 PPGLs (13 cluster 1, 18 cluster 2, 9 sporadic) were delineated using a 41% adaptive threshold of SUVpeak ([18F]FDG-PET) and manually (low-dose CT; ldCT). Using PyRadiomics, 211 radiomic features were extracted. Stratified 5-fold cross-validation for the identification of the genetic cluster was performed using multinomial logistic regression with dimensionality reduction incorporated per fold. Classification performances of biochemistry, SUVmax and PET(/CT) radiomic models were compared and presented as mean (multiclass) test AUCs over the five folds. Results were validated using a sham experiment, randomly shuffling the outcome labels. RESULTS: The model with biochemistry only could identify the genetic cluster (multiclass AUC 0.60). The three-factor PET model had the best classification performance (multiclass AUC 0.88). A simplified model with only SUVmax performed almost similarly. Addition of ldCT features and biochemistry decreased the classification performances. All sham AUCs were approximately 0.50. CONCLUSION: PET radiomics achieves a better identification of PPGLs compared to biochemistry, SUVmax, ldCT radiomics and combined approaches, especially for the differentiation of sporadic PPGLs. Nevertheless, a model with SUVmax alone might be preferred clinically, weighing model performances against laborious radiomic analysis. The limited added value of radiomics to the overall classification performance for PPGL should be validated in a larger external cohort. KEY POINTS: • Radiomics derived from [18F]FDG-PET/CT has the potential to improve the identification of the genetic clusters of pheochromocytomas and paragangliomas. • A simplified model with SUVmax only might be preferred clinically, weighing model performances against the laborious radiomic analysis. • Cluster 1 and 2 PPGLs generally present distinctive characteristics that can be captured using [18F]FDG-PET imaging. Sporadic PPGLs appear more heterogeneous, frequently resembling cluster 2 PPGLs and occasionally resembling cluster 1 PPGLs.

Predicting surgical outcome in posterior retroperitoneoscopic adrenalectomy with the aid of a preoperative nomogram.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) has several advantages over transperitoneal laparoscopic adrenalectomy (TLA) regarding operative time, blood loss, postoperative pain, and recovery. However, it can be a technically challenging procedure. To improve patient selection for PRA, we developed a preoperative nomogram to predict operative time. METHODS: All consecutive patients with tumors of ≤ 7 cm and a body mass index (BMI) of < 35 kg/m2 undergoing unilateral PRA between February 2011 and March 2020 were included in the study. The primary outcome was operative time as surrogate endpoint for surgical complexity. Using ten patient variables, an optimal prediction model was created, with a best subsets regression analysis to find the best one-variable up to the best seven-variable model. RESULTS: In total 215 patients were included, with a mean age of 52 years and mean tumor size of 2.4 cm. After best subsets regression analysis, a four-variable nomogram was selected and calibrated. This model included sex, pheochromocytoma, BMI, and perinephric fat, which were all individually significant predictors. This model showed an ideal balance between predictive power and applicability, with an R2 of 38.6. CONCLUSIONS: A four-variable nomogram was developed to predict operative time in PRA, which can aid the surgeon to preoperatively identify suitable patients for PRA. If the nomogram predicts longer operative time and therefore a more complex operation, TLA should be considered as an alternative approach since it provides a larger working space. Also, the nomogram can be used for training purposes to select patients with favorable characteristics when learning this surgical approach.

Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo.

A molecular hallmark in Parkinson's disease (PD) pathogenesis are α-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of α-synuclein. Here, we investigated the effects of CDNF on α-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with α-synuclein with a KD = 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of α-synuclein fibrils and induces the formation of insoluble phosphorylated α-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with α-synuclein fibrils, though it did not reduce the number of phosphorylated α-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with α-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.

Chronic postsurgical pain after minimally invasive adrenalectomy: prevalence and impact on quality of life.

BACKGROUND: Minimally invasive adrenalectomy is the standard of care for small adrenal tumours. Both the transperitoneal lateral approach and posterior retroperitoneal approach are widely used and have been proven to be safe and effective. However, the prevalence of chronic postsurgical pain has not been specifically investigated in previous studies. The primary goal of this study was to identify the prevalence of chronic postsurgical pain after minimally invasive adrenalectomy. METHODS: A cross-sectional study was performed among all consecutive patients who had undergone minimally invasive adrenalectomy in a single university medical centre. The primary outcome was the prevalence of chronic postsurgical pain. Secondary outcomes were the prevalence of localized hypoesthesia, risk factors for the development of chronic postsurgical pain, and the Health-Related Quality of Life. Three questionnaires were used to measure the prevalence and severity of chronic postsurgical pain, hypoesthesia, and Health-Related Quality of Life. Logistic regression analysis was performed to determine risk factors for development of chronic postsurgical pain. RESULTS: Six hundred two patients underwent minimally invasive adrenalectomy between January 2007 and September 2019, of whom 328 signed informed consent. The prevalence of chronic postsurgical pain was 14.9%. In the group of patients with chronic postsurgical pain, 33% reported hypoesthesia as well. Young age was a significant predictor for developing chronic postsurgical pain. The prevalence of localized hypoesthesia was 15.2%. In patients with chronic postsurgical pain, Health-Related Quality of Life was significantly lower, compared to patients without pain. CONCLUSIONS: The prevalence of chronic postsurgical pain following minimally invasive adrenalectomy is considerable. Furthermore, the presence of chronic postsurgical pain was correlated with a significant and clinically relevant lower Health-Related Quality of Life. These findings should be included in the preoperative counselling of the patient. In the absence of evidence for effective treatment in established chronic pain, prevention should be the key strategy and topic of future research.

Evaluation of a Novel Oncolytic Adenovirus Silencing SYVN1.

Oncolytic adenoviruses are promising new anticancer agents. To realize their full anticancer potential, they are being engineered to express therapeutic payloads. Tumor suppressor p53 function contributes to oncolytic adenovirus activity. Many cancer cells carry an intact TP53 gene but express p53 inhibitors that compromise p53 function. Therefore, we hypothesized that oncolytic adenoviruses could be made more effective by suppressing p53 inhibitors in selected cancer cells. To investigate this concept, we attenuated the expression of the established p53 inhibitor synoviolin (SYVN1) in A549 lung cancer cells by RNA interference. Silencing SYVN1 inhibited p53 degradation, thereby increasing p53 activity, and promoted adenovirus-induced A549 cell death. Based on these observations, we constructed a new oncolytic adenovirus that expresses a short hairpin RNA against SYVN1. This virus killed A549 cells more effectively in vitro and inhibited A549 xenograft tumor growth in vivo. Surprisingly, increased susceptibility to adenovirus-mediated cell killing by SYVN1 silencing was also observed in A549 TP53 knockout cells. Hence, while the mechanism of SYVN1-mediated inhibition of adenovirus replication is not fully understood, our results clearly show that RNA interference technology can be exploited to design more potent oncolytic adenoviruses.

Mitogenomics of Cladocera (Branchiopoda): Marked gene order rearrangements and independent predation roots.

Cladocera (Crustacea: Branchiopoda) is a key group of invertebrates. Despite a long history of phylogenetic research, relationships within this group remain disputed. We here provide new insights based on 15 new mitochondrial genomes obtained from high-throughput sequencing (HTS) and 40 mitogenomes extracted from published HTS datasets. Together with 25 mitogenomes from GenBank, we generated a matrix of 80 mitogenomes, 44 of them belonging to Cladocera. We also obtained a matrix with 168 nuclear orthologous genes to further assess the phylogenetic result from mitogenomes based on published data and one new HTS data ofLeptodora. Maximum likelihood and Bayesian phylogenetic analyses recovered all Branchiopoda orders as monophyletic and supported a sister-group relationship between Anomopoda and Onychopoda, making the taxon Gymnomera paraphyletic and supporting an independent origin of predatory Haplopoda and Onychopoda. The nuclear phylogeny and topological tests also support Gymnomera as paraphyletic, and the nuclear phylogeny strongly supports a sister-group relationship between Ctenopoda and Haplopoda. We provide a fossil-calibrated time tree, congruent with a Carboniferous origin for Cladocera and a subsequent diversification of the crown group of Anomopoda, Onychopoda, and Ctenopoda, at least in the Triassic. Despite their long evolutionary history, non-Cladoceran Branchiopoda exhibited high mitogenome structural stability. On the other hand, 21 out of 24 gene rearrangements occurred within the relatively younger Cladocera. We found the differential base compositional skewness patterns between Daphnia s.s. and Ctenodaphnia, which might be related to the divergence between these taxa. We also provide evidence to support the recent finding that Spinicaudata possesses mitogenomes with inversed compositional skewness without gene rearrangement. Such a pattern has only been reported in Spinicaudata.

Mechanisms of secretion and spreading of pathological tau protein.

Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer's disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.