ABSTRACT
For prostate cancer, the role of elective nodal irradiation (ENI) for cN0 or pN0 patients has been under discussion for years. Considering the recent publications of randomized controlled trials, the prostate cancer expert panel of the German Society of Radiation Oncology (DEGRO) aimed to discuss and summarize the current literature. Modern trials have been recently published for both treatment-naïve patients (POP-RT trial) and patients after surgery (SPPORT trial). Although there are more reliable data to date, we identified several limitations currently complicating the definitions of general recommendations. For patients with cN0 (conventional or PSMA-PET staging) undergoing definitive radiotherapy, only men with high-risk factors for nodal involvement (e.g., cT3a, GS ≥â¯8, PSA ≥â¯20â¯ng/ml) seem to benefit from ENI. For biochemical relapse in the postoperative situation (pN0) and no PSMA imaging, ENI may be added to patients with risk factors according to the SPPORT trial (e.g., GS ≥â¯8; PSA >â¯0.7â¯ng/ml). If PSMA-PET/CT is negative, ENI may be offered for selected men with high-risk factors as an individual treatment approach.
Subject(s)
Prostatic Neoplasms , Radiation Oncology , Male , Humans , Positron Emission Tomography Computed Tomography/methods , Prostate-Specific Antigen , Neoplasm Recurrence, Local , Prostatic Neoplasms/radiotherapyABSTRACT
Brainstem evoked response audiometry (BERA) is the most established and recommended objective audiometric method for the clinical diagnosis of hearing impairment in high-risk infants. It is unclear whether infants with orofacial clefts meet the criteria for the high-risk group. This retrospective cohort study evaluated the need for diagnostic BERA in infants with cleft palate with or without cleft lip by assessing the predisposition to and diagnosis of congenital hearing impairment. Data from 122 patients treated at a single cleft centre were evaluated. BERA was conducted at the time of palate repair at 4-6 months of age. Clinical follow-up was analysed up to 4 years. The presence of a syndrome was examined as a risk factor for congenital hearing impairment. Among the 122 patients, four had congenital sensorineural or mixed hearing loss requiring hearing aids. All affected patients had syndromes in addition to the cleft. Most patients with elevated hearing thresholds had transient conductive hearing loss. Most suspected sensorineural hearing loss initially diagnosed was refuted. However, a higher incidence of sensorineural hearing loss was found in patients with syndromic clefts, supporting the diagnostic use of BERA with initial surgery only in patients with syndromic clefts.
Subject(s)
Cleft Lip , Cleft Palate , Hearing Loss, Sensorineural , Hearing Loss , Infant , Humans , Cleft Lip/surgery , Cleft Palate/complications , Cleft Palate/surgery , Audiometry, Evoked Response , Retrospective Studies , Hearing Loss, Sensorineural/diagnosis , Hearing Loss, Sensorineural/epidemiology , Hearing Loss/epidemiology , Brain StemABSTRACT
BACKGROUND: Deep-learning convolutional neural networks (CNNs) have outperformed even experienced dermatologists in dermoscopic melanoma detection under controlled conditions. It remains unexplored how real-world dermoscopic image transformations affect CNN robustness. OBJECTIVES: To investigate the consistency of melanoma risk assessment by two commercially available CNNs to help formulate recommendations for current clinical use. METHODS: A comparative cohort study was conducted from January to July 2022 at the Department of Dermatology, University Hospital Basel. Five dermoscopic images of 116 different lesions on the torso of 66 patients were captured consecutively by the same operator without deliberate rotation. Classification was performed by two CNNs (CNN-1/CNN-2). Lesions were divided into four subgroups based on their initial risk scoring and clinical dignity assessment. Reliability was assessed by variation and intraclass correlation coefficients. Excisions were performed for melanoma suspicion or two consecutively elevated CNN risk scores, and benign lesions were confirmed by expert consensus (n = 3). RESULTS: 117 repeated image series of 116 melanocytic lesions (2 melanomas, 16 dysplastic naevi, 29 naevi, 1 solar lentigo, 1 suspicious and 67 benign) were classified. CNN-1 demonstrated superior measurement repeatability for clinically benign lesions with an initial malignant risk score (mean variation coefficient (mvc): CNN-1: 49.5(±34.3)%; CNN-2: 71.4(±22.5)%; p = 0.03), while CNN-2 outperformed for clinically benign lesions with benign scoring (mvc: CNN-1: 49.7(±22.7)%; CNN-2: 23.8(±29.3)%; p = 0.002). Both systems exhibited lowest score consistency for lesions with an initial malignant risk score and benign assessment. In this context, averaging three initial risk scores achieved highest sensitivity of dignity assessment (CNN-1: 94%; CNN-2: 89%). Intraclass correlation coefficients indicated 'moderate'-to-'good' reliability for both systems (CNN-1: 0.80, 95% CI:0.71-0.87, p < 0.001; CNN-2: 0.67, 95% CI:0.55-0.77, p < 0.001). CONCLUSIONS: Potential user-induced image changes can significantly influence CNN classification. For clinical application, we recommend using the average of three initial risk scores. Furthermore, we advocate for CNN robustness optimization by cross-validation with repeated image sets. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04605822).
Subject(s)
Dermoscopy , Melanoma , Neural Networks, Computer , Skin Neoplasms , Humans , Melanoma/diagnostic imaging , Melanoma/pathology , Dermoscopy/methods , Skin Neoplasms/diagnostic imaging , Skin Neoplasms/pathology , Prospective Studies , Male , Female , Middle Aged , Reproducibility of Results , Adult , Aged , Risk Assessment , Deep Learning , Dysplastic Nevus Syndrome/pathology , Dysplastic Nevus Syndrome/diagnostic imagingABSTRACT
OBJECTIVE: Two-dimensional (2D) transvaginal ultrasound (TVS) is an accessible and cost-effective diagnostic tool for the detection of adenomyosis. Different ultrasound features related to adenomyosis have been described, but the predictive value of each ultrasound sign and their combinations requires further investigation. We aimed to analyze the accuracy of 2D-TVS and describe possible combinations of ultrasound signs with a high predictive value in the diagnosis of adenomyosis. METHODS: This was a prospective multicenter study of patients scheduled for laparoscopic hysterectomy who had been examined using standardized 2D-TVS at nine expert centers specializing in the diagnosis and treatment of endometriosis. 2D-TVS examination included nine typical adenomyosis ultrasound features, comprising heterogeneous myometrium, myometrial linear striations, myometrial cysts, subendometrial microcysts, asymmetrical myometrial thickening, uterine enlargement, the 'question mark sign', thickening of the junctional zone and hyperechoic myometrial spots, in order to predict or exclude the presence of adenomyosis. Ultrasound examination results were compared with histology after hysterectomy. The diagnostic reliability of the nine ultrasound signs and their combinations, and the influence of concurrent fibroids on the accuracy of the results, were analyzed. RESULTS: A total of 202 patients were enrolled into the study. Histopathological examination revealed adenomyosis in 130 patients (64.4%). The accuracy of prediction of adenomyosis by 2D-TVS examination using all signs was 63.4% (positive predictive value, 71.5%; negative predictive value, 48.6%; sensitivity, 71.5%; specificity, 48.6%). Heterogeneous myometrium, myometrial cysts, subendometrial microcysts and hyperechoic myometrial spots showed the highest accuracy (55.7-62.1%) as individual ultrasound signs for the prediction of adenomyosis. The combination of the most accurate ultrasound signs (subendometrial microcysts, myometrial cysts and heterogeneous myometrium) improved the specificity of prediction (86.1%) when compared with that of these three single markers (35.2-81.7%). Uterine enlargement and asymmetry showed both low sensitivity (60.8% and 52.3%, respectively) and specificity (41.7% and 49.3%, respectively) as individual sonographic signs. CONCLUSIONS: Heterogeneous myometrium, myometrial cysts, subendometrial microcysts and hyperechoic myometrial spots showed the highest accuracy for the detection of adenomyosis in this study, while uterine enlargement and asymmetry led to high false-positive and false-negative results. A combination of ultrasound features including the most accurate signs increases specificity. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Adenomyosis , Cysts , Endometriosis , Female , Humans , Adenomyosis/diagnostic imaging , Endometriosis/diagnostic imaging , Endometriosis/pathology , Myometrium/diagnostic imaging , Myometrium/pathology , Prospective Studies , Reproducibility of Results , Sensitivity and Specificity , Ultrasonography/methodsABSTRACT
As the demand for poultry meat continues to rise, industry production is constantly challenged with obtaining consumer needs. Integrators have answered this increasing demand by improving the growth rate of broilers allowing for increased production efficiently. The resulting broiler produces higher yields and a larger quantity of fresh poultry to satisfy consumer needs. However, this increase in efficiency has cost integrators as new quality issues continue to manifest through global production. Therefore, the objective of the current experiment was to evaluate the effect of genetic strain (standard and high yielding) and target weight on meat quality attributes such as pH, water holding capacity (WHC), and tenderness, alongside meat quality defects such as breast and tender myopathies. In the current study, 1,800 broilers from 4 commercial strains (2 high breast yielding (HY) and 2 standard yielding (SY) were raised sex separate to evaluate meat quality trends over time at 6 previously defined market weights. Birds were processed at weights ranging from 2,043 to 4,313 g in 454 g increments. HY strains produced higher breast and tender yields than those of SY strains (P < 0.05). There was an increase in breast and tender yield as target weight increased (P < 0.05) for both HY and SY strains. Differences were observed between strains for all fillet dimensions (P < 0.05); however, these measurements increased as target weight increased as expected. Woody breast (WB) had a higher severity (P < 0.05) in HY strains over SY strains, for both males and females. Differences were observed in white striping (WS; P < 0.05) for females in both strains, but no differences were observed in males. A main effect of target was noticed for both WB and WS (P < 0.05), expressing increased severity as target weight increased. Shear values were influenced more by target weight (P < 0.05), but inconsistent differences were observed between HY and SY groups. Meullenet-Owens Razor Shear (MORS) energy values increased slightly as target weights increased (P < 0.05) from 2,951 to 4,313 g in both males and females, but differences were minor and inconsistent with the smaller carcass weights. The MORS peak counts generally increased as target weight increased for both sexes. While strain had minimal effects on meat quality attributes, processing weight had a greater influence on quality, specifically muscle myopathies, WHC, and shear properties.
Subject(s)
Chickens , Muscular Diseases , Female , Male , Animals , Chickens/physiology , Muscular Diseases/veterinary , Meat/analysis , Muscles , Water , Pectoralis MusclesABSTRACT
We demonstrate that hard dijet production via coherent inelastic diffraction is a promising channel for probing gluon saturation at the Electron-Ion Collider. By inelastic diffraction, we mean a process in which the two hard jets-a quark-antiquark pair generated by the decay of the virtual photon-are accompanied by a softer gluon jet, emitted by the quark or the antiquark. This process can be described as the elastic scattering of an effective gluon-gluon dipole. The cross section takes a factorized form, between a hard factor and a unintegrated ("Pomeron") gluon distribution describing the transverse momentum imbalance between the hard dijets. The dominant contribution comes from the black disk limit and leads to a dijet imbalance of the order of the target saturation momentum Q_{s} evaluated at the rapidity gap. Integrating out the dijet imbalance, we obtain a collinear factorization where the initial condition for the Dokshitzer-Gribov-Lipatov-Altarelli-Parisi evolution is set by gluon saturation.
ABSTRACT
Delirium occurs commonly following major non-cardiac and cardiac surgery and is associated with: postoperative mortality; postoperative neurocognitive dysfunction; increased length of hospital stay; and major postoperative complications and morbidity. The aim of this study was to investigate the effect of peri-operative administration of dexmedetomidine on the incidence of postoperative delirium in non-cardiac and cardiac surgical patients. In this randomised, double-blind placebo-controlled trial we included 63 patients aged ≥ 60 years undergoing major open abdominal surgery or coronary artery bypass graft surgery with cardiopulmonary bypass. The primary outcome was the incidence of postoperative delirium, as screened for with the Confusion Assessment Method. Delirium assessment was performed twice daily until postoperative day 5, at the time of discharge from hospital or until postoperative day 14. We found that dexmedetomidine was associated with a reduced incidence of postoperative delirium within the first 5 postoperative days, 43.8% vs. 17.9%, p = 0.038. Severity of delirium, screened with the Intensive Care Delirium Screening Checklist, was comparable in both groups, with a mean maximum score of 1.54 vs. 1.68, p = 0.767. No patients in the dexmedetomidine group died while five (15.6%) patients in the placebo group died, p = 0.029. For patients aged ≥ 60 years undergoing major cardiac or non-cardiac surgery, we conclude that the peri-operative administration of dexmedetomidine is associated with a lower incidence of postoperative delirium.
Subject(s)
Dexmedetomidine/therapeutic use , Emergence Delirium/epidemiology , Emergence Delirium/prevention & control , Hypnotics and Sedatives/therapeutic use , Perioperative Care/methods , Surgical Procedures, Operative , Aged , Berlin/epidemiology , Double-Blind Method , Female , Humans , Incidence , Length of Stay/statistics & numerical data , Male , Prospective StudiesABSTRACT
BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane. CASE PRESENTATION: We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70-1)_(212 + 1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months. CONCLUSIONS: As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.
Subject(s)
Cholestasis, Intrahepatic , Cholestasis , Citrullinemia , Citrullinemia/diagnosis , Citrullinemia/genetics , Female , Humans , Infant , Infant, Newborn , Male , Mitochondrial Membrane Transport Proteins/genetics , MutationABSTRACT
We investigate properties of the particle distribution near the tip of one-dimensional branching random walks at large times t, focusing on unusual realizations in which the rightmost lead particle is very far ahead of its expected position, but still within a distance smaller than the diffusion radius â¼sqrt[t]. Our approach consists in a study of the generating function G_{Δx}(λ)=∑_{n}λ^{n}p_{n}(Δx) for the probabilities p_{n}(Δx) of observing n particles in an interval of given size Δx from the lead particle to its left, fixing the position of the latter. This generating function can be expressed with the help of functions solving the Fisher-Kolmogorov-Petrovsky-Piscounov (FKPP) equation with suitable initial conditions. In the infinite-time and large-Δx limits, we find that the mean number of particles in the interval grows exponentially with Δx, and that the generating function obeys a nontrivial scaling law, depending on Δx and λ through the combined variable [Δx-f(λ)]^{3}/Δx^{2}, where f(λ)≡-ln(1-λ)-ln[-ln(1-λ)]. From this property, one may conjecture that the growth of the typical particle number with the size of the interval is slower than exponential, but, surprisingly enough, only by a subleading factor at large Δx. The scaling we argue is consistent with results from a numerical integration of the FKPP equation.
ABSTRACT
AIMS: Considering that people with type 1 diabetes and impaired awareness of hypoglycaemia (IAH) have a delayed perception of hypoglycaemia, the question arises whether they perform scans later in case of hypoglycaemia than people without IAH. We assessed whether time to performing a scan after reaching hypoglycaemia while using a flash glucose monitoring (flash GM) system is different in people with IAH compared with people without IAH. METHODS: Ninety-two people with type 1 diabetes [mean (± sd) age 42 ± 14 years, HbA1c 57 ± 9 mmol/mol] using a flash GM system for 3 months were included. Flash GM data were assessed for time until scan after reaching hypoglycaemia level 1 (< 3.9 mmol/l) and level 2 (< 3.0 mmol/l) and compared for type 1 diabetes with vs. without IAH via unpaired t-test/Mann-Whitney U test (P < 0.05). RESULTS: Significant differences were found only for the delay between reaching hypoglycaemia and scan between people with and without IAH for Gold score [hypoglycaemia level 1: IAH 78 (51-105) min vs. without IAH 63 (42-89) min, P = 0.03; night-time hypoglycaemia level 2: IAH 140 (107-227) min vs. without IAH 96 (41-155) min, P = 0.004] and Pedersen-Bjergaard score [hypoglycaemia level 1: IAH 76 (52-97) min vs. without IAH 54 (38-71) min, P = 0.011; night-time hypoglycaemia level 1: IAH 132 (79-209) min vs. without IAH 89 (59-143) min, P = 0.011; night-time hypoglycaemia level 2: IAH 134 (66-212) min vs. without IAH 80 (37-131) min, P = 0.002). Data are shown as median (i.q.r.). CONCLUSIONS: Time until scan after reaching hypoglycaemia might be an objective assessment tool for IAH, but needs to be investigated comprehensively in future studies.
Subject(s)
Awareness , Blood Glucose Self-Monitoring/methods , Diabetes Mellitus, Type 1/drug therapy , Hypoglycemia/diagnosis , Hypoglycemic Agents/adverse effects , Insulin/adverse effects , Reaction Time , Adult , Diabetes Mellitus, Type 1/physiopathology , Female , Humans , Hypoglycemia/chemically induced , Male , Middle Aged , Prospective Studies , Severity of Illness Index , Time FactorsABSTRACT
OBJECTIVE: The in vitro elution of the active substances etonogestrel (ETO) and ethinylestradiol (EE) of Ornibel® (a vaginal delivery system) was determined after a deliberate breakage of the vaginal contraceptive ring and compared to the standard elution and hormone release of intact rings under the same experimental conditions. MATERIALS AND METHODS: Ornibel® intact and broken vaginal rings were placed in a dissolution buffer and subject to a repetitive sampling of ETO and EE following a standardized in vitro elution (IVE) procedure for 21 days. The hormone dissolution profile was determined by HPLC using a fully validated analytical method. In a second study, rings were broken after day seven, and their elution profiles were compared to that of intact rings. For all utilized batches, the stability conditions established were 24 months at 5°C. Furthermore, no special storage conditions are needed. RESULTS: The instantaneous elution on day 1 of ETO and EE for intact rings were 119±8 µg/day and 15±1 µg/day, respectively (mean ± SD), which was non-significantly different to the immediate release of ETO and EE for broken rings (118±4 µg/day and 14±1 µg/day). The average elution profile for days 2-20 were 132±5 µg/day and 18±1 µg/day (ETO/EE, intact rings) and 132±4 µg/day and 19±1 µg/day (ETO/EE, broken rings) respectively. On day 21, the elution of ETO and EE was numerically similar 111±5 (±4) µg/day and 18±1 µg/day) for both intact and broken rings. The IVE results from intact rings and vaginal rings deliberately cut on day seven similarly did not differ in their release of ETO and EE. CONCLUSIONS: Our study concludes that the hormonal release of ETO and EE from Ornibel® are similar for intact and broken vaginal rings under standardized in vitro conditions.
Subject(s)
Contraceptive Agents, Female/analysis , Contraceptive Devices, Female , Desogestrel/analysis , Ethinyl Estradiol/analysis , Drug Delivery Systems , Female , Humans , Materials TestingABSTRACT
Cancer metastasis is the cause of most cancer related deaths and many cancers are becoming resistant to current therapies. An alternative approach is to investigating signalling pathways that cause cancer cell migration such as chemokine signalling pathways. Such downstream signalling proteins are PKC and PKD. Therefore, we investigated the role of these two proteins in CXCL12 mediated PC3 prostate cancer migration. Whereas PKC and PKD inhibitors do not affect the release of calcium in PC3 prostate cancer cells, both are involved in migration, particularly inhibition of the atypical PKC isoform PKCζ causes the greatest reduction in PC3 cell migration. Classical and/or Novel PKC isoform inhibition changes the shape of the PC3 cells, they show a more rounded morphology, whereas PKD inhibition causes prostate cancer cell to elongate. PKCζ inhibition causes the enlargement of PC3 area possibly due to dysregulated actin cytoskeletal control. These results highlight the importance of verifying which signalling proteins, in which cell and in which chemokine signalling cascade enable cancer cellular migration.
Subject(s)
Chemokine CXCL12/metabolism , Prostatic Neoplasms/metabolism , Protein Kinase C/metabolism , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Movement/drug effects , Cell Proliferation/drug effects , Cell Survival/drug effects , Chemokine CXCL12/antagonists & inhibitors , Drug Screening Assays, Antitumor , Humans , Male , PC-3 Cells , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Tumor Cells, CulturedABSTRACT
Vincristine is an antineoplastic substance that is part of many chemotherapy regimens, used especially for the treatment of a variety of pediatric cancers including leukemias and brain tumors. Unfortunately, many vincristine-treated patients develop peripheral neuropathy, a side effect characterized by sensory, motoric, and autonomic symptoms. The sensory symptoms include pain, in particular hypersensitivity to light touch, as well as loss of sensory discrimination to detect vibration and touch. The symptoms of vincristine-induced neuropathy are only poorly controlled by currently available analgesics and therefore often necessitate dose reductions or even cessation of treatment. The aim of this study was to identify new therapeutic targets for the treatment of vincristine-induced peripheral neuropathy (VIPN) by combining behavioral experiments, histology, and pharmacology after vincristine treatment. Local intraplantar injection of vincristine into the hind paw caused dose- and time-dependent mechanical hypersensitivity that developed into mechanical hyposensitivity at high doses, and lead to a pronounced, dose-dependent infiltration of immune cells at the site of injection. Importantly, administration of minocycline effectively prevented the development of mechanical hypersensitivity and infiltration of immune cells in mouse models of vincristine induce peripheral neuropathy (VIPN) based on intraperitoneal or intraplantar administration of vincristine. Similarly, Toll-like receptor 4 knockout mice showed diminished vincristine-induced mechanical hypersensitivity and immune cell infiltration, while treatment with the anti-inflammatory meloxicam had no effect. These results provide evidence for the involvement of Toll-like receptor 4 in the development of VIPN and suggest that minocycline and/or direct Toll-like receptor 4 antagonists may be an effective preventative treatment for patients receiving vincristine.
ABSTRACT
We investigate the P_{T}-broadening effects in dilepton production through photon-photon scattering in heavy ion collisions. The QED multiple interaction effect with the medium is found to be consistent with the recent observation of a low transverse momentum lepton pair from the ATLAS Collaboration at the LHC. We further comment on the magnetic broadening effect and point out a number of ways to disentangle these two mechanisms. In particular, the rapidity dependence of the P_{T}-broadening effect provides a unique probe to the magnetic effect.
ABSTRACT
Parkinson's disease (PD) is the second most frequent neurodegenerative disorder in the old population. Among its monogenic variants, a frequent cause is a mutation in the Parkin gene (Prkn). Deficient function of Parkin triggers ubiquitous mitochondrial dysfunction and inflammation in the brain, but it remains unclear how selective neural circuits become vulnerable and finally undergo atrophy. We attempted to go beyond previous work, mostly done in peripheral tumor cells, which identified protein targets of Parkin activity, an ubiquitin E3 ligase. Thus, we now used aged Parkin-knockout (KO) mouse brain for a global quantification of ubiquitylated peptides by mass spectrometry (MS). This approach confirmed the most abundant substrate to be VDAC3, a mitochondrial outer membrane porin that modulates calcium flux, while uncovering also >3-fold dysregulations for neuron-specific factors. Ubiquitylation decreases were prominent for Hippocalcin (HPCA), Calmodulin (CALM1/CALML3), Pyruvate Kinase (PKM2), sodium/potassium-transporting ATPases (ATP1A1/2/3/4), the Rab27A-GTPase activating protein alpha (TBC1D10A) and an ubiquitin ligase adapter (DDB1), while strong increases occurred for calcium transporter ATP2C1 and G-protein subunits G(i)/G(o)/G(Tr). Quantitative immunoblots validated elevated abundance for the electrogenic pump ATP1A2, for HPCA as neuron-specific calcium sensor, which stimulates guanylate cyclases and modifies axonal slow afterhyperpolarization (sAHP), and for the calcium-sensing G-protein GNA11. We assessed if compensatory molecular regulations become insufficient over time, leading to functional deficits. Patch clamp experiments in acute Parkin-KO brain slices indeed revealed alterations of the electrophysiological properties in aged noradrenergic locus coeruleus (LC) neurons. LC neurons of aged Parkin-KO brain showed an acceleration of the spontaneous pacemaker frequency, a reduction in sAHP and shortening of action potential duration, without modulation of KCNQ potassium currents. These findings indicate altered calcium-dependent excitability in a PARK2 model of PD, mediated by diminished turnover of potential Parkin targets such as ATP1A2 and HPCA. The data also identified further novel Parkin substrate candidates like SIRT2, OTUD7B and CUL5. Our elucidation of neuron-specific mechanisms of PD pathogenesis helps to explain the known exceptional susceptibility of noradrenergic and dopaminergic projections to alterations of calcium homeostasis and its mitochondrial buffering.
Subject(s)
Adrenergic Neurons/metabolism , Brain/metabolism , GTP-Binding Protein alpha Subunits/metabolism , Hippocalcin/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Ubiquitin-Protein Ligases/metabolism , Animals , Mass Spectrometry , Mice , Mice, Knockout , Mitochondria/metabolism , Mitochondrial Membrane Transport Proteins/metabolism , Patch-Clamp Techniques , Ubiquitin-Protein Ligases/genetics , Voltage-Dependent Anion Channels/metabolismABSTRACT
AIMS: To evaluate the sensor performance of the FreeStyle Libre intermittently viewed continuous glucose monitoring system using reference blood glucose levels during moderate-intensity exercise while on either full or reduced basal insulin dose in people with Type 1 diabetes. METHODS: Ten participants with Type 1 diabetes [four women, mean ± sd age 31.4 ± 9.0 years, BMI 25.5±3.8 kg/m2 , HbA1c 55±7 mmol/mol (7.2±0.6%)] exercised on a cycle ergometer for 55 min at a moderate intensity for 5 consecutive days at the clinical research facility, while receiving either their usual or a 75% basal insulin dose. After a 4-week washout period, participants performed the second exercise period having switched to the alternative basal insulin dose. During exercise, reference capillary blood glucose values were analysed using the fully enzymatic-amperometric method and compared with the interstitial glucose values obtained. Intermittently viewed continuous glucose monitoring accuracy was analysed according to median (interquartile range) absolute relative difference, and Clarke error grid and Bland-Altman analysis for overall glucose levels during exercise, stratified by glycaemic range and basal insulin dosing scheme (P<0.05). RESULTS: A total of 845 glucose values were available during exercise to evaluate intermittently viewed continuous glucose monitoring sensor performance. The median (interquartile range) absolute relative difference between the reference values and those obtained by the sensor across the glycaemic range overall was 22 (13.9-29.7)%, and was 36.3 (24.2-45.2)% during hypoglycaemia, 22.8 (14.6-30.6)% during euglycaemia and 15.4 (9-21)% during hyperglycaemia. Usual basal insulin dose was associated with a worse sensor performance during exercise compared with the reduced (75%) basal insulin dose [median (interquartile range) absolute relative difference: 23.7 (17.2-30.7)% vs 20.5 (12-28.1)%; P<0.001). CONCLUSIONS: The intermittently viewed continuous glucose monitoring sensor showed diminished accuracy during exercise. Absolute glucose readings derived from the sensor should be used cautiously and need confirmation by additional finger-prick blood glucose measurements.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 1/blood , Equipment and Supplies , Exercise/physiology , Adult , Biosensing Techniques/instrumentation , Biosensing Techniques/standards , Blood Glucose Self-Monitoring/instrumentation , Cross-Over Studies , Diabetes Mellitus, Type 1/drug therapy , Dose-Response Relationship, Drug , Equipment Design , Equipment and Supplies/standards , Female , Humans , Insulin/administration & dosage , Insulin Infusion Systems , Male , Predictive Value of Tests , Young AdultABSTRACT
Following publication of the article, the author named as "B Dey", wished to point out that his full name is "Bijan K. Dey". This was not reflected in the typesetting of the article, and as a consequence the article is not visible on Pub Med when a search is conducted on his full name.