ABSTRACT
Background: Current standard treatment concepts in head and neck squamous cell carcinoma (HNSCC) are based on former studies using 2D and 3D treatment plans. However, modern radiation techniques allow for a more precise and individual dose application. Therefore, in a clearly defined patient population, de-intensified risk-adapted radiation is investigated. Methods: Patients with newly diagnosed HNSCC after surgery (with resection margins ≥1 mm and cM0) with the following tumor stages (TNM 7th Edition) were eligible for the study: oral cavity, oropharynx, or larynx: pT1-3, pN0-pN2b; hypopharynx: pT1-2, pN1. The patients should have either a low risk of local recurrence [≤pT2, resection margin ≥5 mm, no peritumoral lymphangiosis (L0), and no perineural invasion] or contralateral lymph node metastasis (≤3 ipsilateral lymph node metastases, in case of well-lateralized oropharyngeal or oral cavity cancer contralateral cN0, otherwise pN0). Patients were assigned to three different treatment regimes with reduction of the treated volume, radiation dose, or both, according to tumor stage and results of surgery performed. The primary objective was to show an LRR of <10% after 2 years. Findings: A total of 150 patients were enrolled. Tumor localizations were as follows: n = 53 (35.3%), oral cavity; n = 94 (62.7%), oropharynx (82% HPV-positive); n = 2 (1.3%), hypopharynx; and n = 1 (0.7%), larynx. A total of 61 patients (41.0%) were stage IVA, 81 (54.0%) were stage III, and 8 (5.3%) were stage II. Median follow-up was 36 months. Cumulative incidence of 2y-LRR was 5.6% (95% CI: 1.7%-9.2%) in the whole study population and 14.1% (95% CI: 3.8%-23.2%) in patients with oral cavity cancer. Cumulative incidence of 2y-LRR in non-irradiated or dose-reduced regions was 3.5% (95% CI: 0.4%-6.5%). After 2 years, disease-free survival was 92% (95% CI: 87%-96%) and overall survival was 94% (95% CI: 90%-98%) for the complete study cohort. Acute III° toxicity was as follows: dysphagia, 30%; xerostomia, 7%; mucositis, 19%; and dermatitis, 4%. Dysphagia and xerostomia decrease over time. After 27 months, late dysphagia III° and xerostomia II° were 1% and 9%, respectively. Interpretation: The study met its primary objective. De-intensification of postoperative radiotherapy irrespective of HPV status in a predefined patient population is associated with a favorable toxicity profile without compromising LRR. In an unplanned subgroup analysis, a significantly increased risk of LRR was observed in patients with oral cavity cancer. In these patients, de-intensified radiotherapy should be applied with caution.
ABSTRACT
Background: Arterio-venous fistulas (AVF) are used as first-line access for hemodialysis (HD) in the pediatric population. The aim of this investigation was to describe a single-center experience in the creation of AVF, together with its patency in children. Methods: This single-center retrospective study included all patients aged ≤18 years with AVFs created between 1993 and 2023. The collected data included patients' demographics, hemodialysis history, intraoperative data, and required reinterventions in order to determine the impact of these variables on primary, primary-assisted, and secondary patency. Results: Fifty-seven patients were analyzed with a median age of 15 years (range, 7-18 years). Fifty-four forearm and four upper arm fistulas were performed. The median follow-up was 6.9 years (range, 0-23 years). The primary failure rate was 10.5%. The primary patency rate was 67.6%, 53.6%, 51.4%, and 38.1% after 1, 3, 5, and 10 years; primary-assisted patency was 72.9%, 62.8%, 60.6%, and 41.5%; and secondary patency was 87.3%, 81.3%, 76.8%, and 66.6% after 1, 3, 5, and 10 years in the studied population. Conclusions: AVFs showed an acceptable rate of primary failure and excellent long-term patency. In this context, AVFs are an appropriate option for HD access, especially in pediatric patients.
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Commentaries about long-term potentiation (LTP) generally proceed with an implicit assumption that largely the same physiological effect is sampled across different experiments. However, this is clearly not the case. We illustrate the point by comparing LTP in the CA3 projections to CA1 with the different forms of potentiation in the dentate gyrus. These studies lead to the hypothesis that specialized properties of CA1-LTP are adaptations for encoding unsupervised learning and episodic memory, whereas the dentate gyrus variants subserve learning that requires multiple trials and separation of overlapping bodies of information. Recent work has added sex as a second and somewhat surprising dimension along which LTP is also differentiated. Triggering events for CA1-LTP differ between the sexes and the adult induction threshold is significantly higher in females; these findings help explain why males have an advantage in spatial learning. Remarkably, the converse is true before puberty: Females have the lower LTP threshold and are better at spatial memory problems. A mechanism has been identified for the loss-of-function in females but not for the gain-of-function in males. We propose that the many and disparate demands of natural environments, with different processing requirements across ages and between sexes, led to the emergence of multiple LTPs. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.
Subject(s)
Long-Term Potentiation , Animals , Female , Humans , Male , CA1 Region, Hippocampal/physiology , CA3 Region, Hippocampal/physiology , Dentate Gyrus/physiology , Long-Term Potentiation/physiology , Memory/physiology , Sex FactorsABSTRACT
Context contributes to multiple aspects of human episodic memory including segmentation and retrieval. The present studies tested if, in adult male and female mice, context influences the encoding of odors encountered in a single unsupervised sampling session of the type used for the routine acquisition of episodic memories. The three paradigms used differed in complexity (single vs. multiple odor cues) and period from sampling to testing. Results show that males consistently encode odors in a context-dependent manner: the mice discriminated novel from previously sampled cues when tested in the chamber of initial cue sampling but not in a distinct yet familiar chamber. This was independent of the interval between cue encounters or the latency from initial sampling to testing. In contrast, female mice acquired both single cues and the elements of multi-cue episodes, but recall of that information was dependent upon the surrounding context only when the cues were presented serially. These results extend the list of episodic memory features expressed by rodents and also introduce a striking and unexpected sex difference in context effects.
ABSTRACT
Men generally outperform women on encoding spatial components of episodic memory whereas the reverse holds for semantic elements. Here we show that female mice outperform males on tests for non-spatial aspects of episodic memory ("what", "when"), suggesting that the human findings are influenced by neurobiological factors common to mammals. Analysis of hippocampal synaptic plasticity mechanisms and encoding revealed unprecedented, sex-specific contributions of non-classical metabotropic NMDA receptor (NMDAR) functions. While both sexes used non-ionic NMDAR signaling to trigger actin polymerization needed to consolidate long-term potentiation (LTP), NMDAR GluN2B subunit antagonism blocked these effects in males only and had the corresponding sex-specific effect on episodic memory. Conversely, blocking estrogen receptor alpha eliminated metabotropic stabilization of LTP and episodic memory in females only. The results show that sex differences in metabotropic signaling critical for enduring synaptic plasticity in hippocampus have significant consequences for encoding episodic memories.
ABSTRACT
BACKGROUND: SARS-CoV-2 variants of concern (VOC) may result in breakthrough infections (BTIs) in vaccinated individuals. The aim of this study was to investigate the effects of full primary (two-dose) COVID-19 vaccination with wild-type-based SARS-CoV-2 vaccines on symptoms and immunogenicity of SARS-CoV-2 VOC BTIs. METHODS: In a longitudinal multicenter controlled cohort study in Bavaria, Germany, COVID-19 vaccinated and unvaccinated non-hospitalized individuals were prospectively enrolled within 14 days of a PCR-confirmed SARS-CoV-2 infection. Individuals were visited weekly up to 4 times, performing a structured record of medical data and viral load assessment. SARS-CoV-2-specific antibody response was characterized by anti-spike-(S)- and anti-nucleocapsid-(N)-antibody concentrations, anti-S-IgG avidity and neutralization capacity. RESULTS: A total of 300 individuals (212 BTIs, 88 non-BTIs) were included with VOC Alpha or Delta SARS-CoV-2 infections. Full primary COVID-19 vaccination provided a significant effectiveness against five symptoms (relative risk reduction): fever (33 %), cough (21 %), dysgeusia (22 %), dizziness (52 %) and nausea/vomiting (48 %). Full primary vaccinated individuals showed significantly higher 50 % inhibitory concentration (IC50) values against the infecting VOC compared to unvaccinated individuals at week 1 (269 vs. 56, respectively), and weeks 5-7 (1,917 vs. 932, respectively) with significantly higher relative anti-S-IgG avidity (78% vs. 27 % at week 4, respectively). CONCLUSIONS: Full primary COVID-19 vaccination reduced symptom frequencies in non-hospitalized individuals with BTIs and elicited a more rapid and longer lasting neutralization capacity against the infecting VOC compared to unvaccinated individuals. These results support the recommendation to offer at least full primary vaccination to all adults to reduce disease severity caused by immune escape-variants.
Subject(s)
COVID-19 Vaccines , COVID-19 , Adult , Humans , COVID-19/prevention & control , Breakthrough Infections , Cohort Studies , Prospective Studies , SARS-CoV-2 , Antibodies, Viral , Immunoglobulin G , VaccinationABSTRACT
BACKGROUND: To analyze regional variations in T2 and T2* relaxation times in wrist joint cartilage and the triangular fibrocartilage complex (TFCC) at 3 and 7 T and to compare values between field strengths. METHODS: Twenty-five healthy controls and 25 patients with chronic wrist pain were examined at 3 and 7 T on the same day using T2- and T2*-weighted sequences. Six different regions of interest (ROIs) were evaluated for cartilage and 3 ROIs were evaluated at the TFCC based on manual segmentation. Paired t-tests were used to compare T2 and T2* values between field strengths and between different ROIs. Spearman's rank correlation was calculated to assess correlations between T2 and T2* time values at 3 and 7 T. RESULTS: T2 and T2* time values of the cartilage differed significantly between 3 and 7 T for all ROIs (p ≤ 0.045), with one exception: at the distal lunate, no significant differences in T2 values were observed between field strengths. T2* values differed significantly between 3 and 7 T for all ROIs of the TFCC (p ≤ 0.001). Spearman's rank correlation between 3 and 7 T ranged from 0.03 to 0.62 for T2 values and from 0.01 to 0.48 for T2* values. T2 and T2* values for cartilage varied across anatomic locations in healthy controls at both 3 and 7 T. CONCLUSION: Quantitative results of T2 and T2* mapping at the wrist differ between field strengths, with poor correlation between 3 and 7 T. Local variations in cartilage T2 and T2* values are observed in healthy individuals. RELEVANCE STATEMENT: T2 and T2* mapping are feasible for compositional imaging of the TFCC and the cartilage at the wrist at both 3 and 7 T, but the clinical interpretation remains challenging due to differences between field strengths and variations between anatomic locations. KEY POINTS: â¢Field strength and anatomic locations influence T2 and T2* values at the wrist. â¢T2 and T2* values have a poor correlation between 3 and 7 T. â¢Local reference values are needed for each anatomic location for reliable interpretation.
Subject(s)
Wrist Joint , Wrist , Humans , Wrist/diagnostic imaging , Wrist Joint/diagnostic imaging , Magnetic Resonance Imaging/methods , CartilageABSTRACT
Neurodevelopmental disorders are frequently linked to mutations in synaptic organizing molecules. MAM domain containing glycosylphosphatidylinositol anchor 1 and 2 (MDGA1 and MDGA2) are a family of synaptic organizers suggested to play an unusual role as synaptic repressors, but studies offer conflicting evidence for their localization. Using epitope-tagged MDGA1 and MDGA2 knock-in mice, we found that native MDGAs are expressed throughout the brain, peaking early in postnatal development. Surprisingly, endogenous MDGA1 was enriched at excitatory, but not inhibitory, synapses. Both shRNA knockdown and CRISPR/Cas9 knockout of MDGA1 resulted in cell-autonomous, specific impairment of AMPA receptor-mediated synaptic transmission, without affecting GABAergic transmission. Conversely, MDGA2 knockdown/knockout selectively depressed NMDA receptor-mediated transmission but enhanced inhibitory transmission. Our results establish that MDGA2 acts as a synaptic repressor, but only at inhibitory synapses, whereas both MDGAs are required for excitatory transmission. This nonoverlapping division of labor between two highly conserved synaptic proteins is unprecedented.
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BACKGROUND: Several randomised, phase 3 trials have investigated the value of different techniques of accelerated partial breast irradiation (APBI) for patients with early breast cancer after breast-conserving surgery compared with whole-breast irradiation. In a phase 3 randomised trial, we evaluated whether APBI using multicatheter brachytherapy is non-inferior compared with whole-breast irradiation. Here, we present the 10-year follow-up results. METHODS: We did a randomised, phase 3, non-inferiority trial at 16 hospitals and medical centres in Austria, Czech Republic, Germany, Hungary, Poland, Spain, and Switzerland. Patients aged 40 years or older with early invasive breast cancer or ductal carcinoma in situ treated with breast-conserving surgery were centrally randomly assigned (1:1) to receive either whole-breast irradiation or APBI using multicatheter brachytherapy. Whole-breast irradiation was delivered in 25 daily fractions of 50 Gy over 5 weeks, with a supplemental boost of 10 Gy to the tumour bed, and APBI was delivered as 30·1 Gy (seven fractions) and 32·0 Gy (eight fractions) of high-dose-rate brachytherapy in 5 days or as 50 Gy of pulsed-dose-rate brachytherapy over 5 treatment days. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was ipsilateral local recurrence, analysed in the as-treated population; the non-inferiority margin for the recurrence rate difference (defined for 5-year results) was 3 percentage points. The trial is registered with ClinicalTrials.gov, NCT00402519; the trial is complete. FINDINGS: Between April 20, 2004, and July 30, 2009, 1328 female patients were randomly assigned to whole breast irradiation (n=673) or APBI (n=655), of whom 551 in the whole-breast irradiation group and 633 in the APBI group were eligible for analysis. At a median follow-up of 10·36 years (IQR 9·12-11·28), the 10-year local recurrence rates were 1·58% (95% CI 0·37 to 2·8) in the whole-breast irradiation group and 3·51% (1·99 to 5·03) in the APBI group. The difference in 10-year rates between the groups was 1·93% (95% CI -0·018 to 3·87; p=0·074). Adverse events were mostly grade 1 and 2, in 234 (60%) of 393 participants in the whole-breast irradiation group and 314 (67%) of 470 participants in the APBI group, at 7·5-year or 10-year follow-up, or both. Patients in the APBI group had a significantly lower incidence of treatment-related grade 3 late side-effects than those in the whole-breast irradiation group (17 [4%] of 393 for whole-breast irradiation vs seven [1%] of 470 for APBI; p=0·021; at 7·5-year or 10-year follow-up, or both). At 10 years, the most common type of grade 3 adverse event in both treatment groups was fibrosis (six [2%] of 313 patients for whole-breast irradiation and three [1%] of 375 patients for APBI, p=0·56). No grade 4 adverse events or treatment-related deaths have been observed. INTERPRETATION: Postoperative APBI using multicatheter brachytherapy after breast-conserving surgery in patients with early breast cancer is a valuable alternative to whole-breast irradiation in terms of treatment efficacy and is associated with fewer late side-effects. FUNDING: German Cancer Aid, Germany.
Subject(s)
Brachytherapy , Breast Neoplasms , Carcinoma, Intraductal, Noninfiltrating , Female , Humans , Breast Neoplasms/pathology , Brachytherapy/adverse effects , Carcinoma, Intraductal, Noninfiltrating/pathology , Mastectomy, Segmental/adverse effects , Treatment Outcome , Neoplasm Recurrence, Local/surgeryABSTRACT
Although sex differences in learning behaviors are well documented, sexual dimorphism in the synaptic processes of encoding is only recently appreciated. Studies in male rodents have built upon the discovery of long-term potentiation (LTP), and acceptance of this activity-dependent increase in synaptic strength as a mechanism of encoding, to identify synaptic receptors and signaling activities that coordinate the activity-dependent remodeling of the subsynaptic actin cytoskeleton that is critical for enduring potentiation and memory. These molecular substrates together with other features of LTP, as characterized in males, have provided an explanation for a range of memory phenomena including multiple stages of consolidation, the efficacy of spaced training, and the location of engrams at the level of individual synapses. In the present report, we summarize these findings and describe more recent results from our laboratories showing that in females the same actin regulatory mechanisms are required for hippocampal LTP and memory but, in females only, the engagement of both modulatory receptors such as TrkB and synaptic signaling intermediaries including Src and ERK1/2 requires neuron-derived estrogen and signaling through membrane-associated estrogen receptor α (ERα). Moreover, in association with the additional ERα involvement, females exhibit a higher threshold for hippocampal LTP and spatial learning. We propose that the distinct LTP threshold in females contributes to as yet unappreciated sex differences in information processing and features of learning and memory.
Subject(s)
Estrogen Receptor alpha , Sex Characteristics , Male , Female , Animals , Neuronal Plasticity , Long-Term Potentiation , Hippocampus , Spatial Learning , SynapsesABSTRACT
Despite its evident importance to learning theory and models, the manner in which the lateral perforant path (LPP) transforms signals from entorhinal cortex to hippocampus is not well understood. The present studies measured synaptic responses in the dentate gyrus (DG) of adult mouse hippocampal slices during different patterns of LPP stimulation. Theta (5 Hz) stimulation produced a modest within-train facilitation that was markedly enhanced at the level of DG output. Gamma (50 Hz) activation resulted in a singular pattern with initial synaptic facilitation being followed by a progressively greater depression. DG output was absent after only two pulses. Reducing release probability with low extracellular calcium instated frequency facilitation to gamma stimulation while long-term potentiation, which increases release by LPP terminals, enhanced within-train depression. Relatedly, per terminal concentrations of VGLUT2, a vesicular glutamate transporter associated with high release probability, were much greater in the LPP than in CA3-CA1 connections. Attempts to circumvent the potent gamma filter using a series of short (three-pulse) 50 Hz trains spaced by 200 ms were only partially successful: composite responses were substantially reduced after the first burst, an effect opposite to that recorded in field CA1. The interaction between bursts was surprisingly persistent (>1.0 s). Low calcium improved throughput during theta/gamma activation but buffering of postsynaptic calcium did not. In all, presynaptic specializations relating to release probability produce an unusual but potent type of frequency filtering in the LPP. Patterned burst input engages a different type of filter with substrates that are also likely to be located presynaptically. KEY POINTS: The lateral perforant path (LPP)-dentate gyrus (DG) synapse operates as a low-pass filter, where responses to a train of 50 Hz, γ frequency activation are greatly suppressed. Activation with brief bursts of γ frequency information engages a secondary filter that persists for prolonged periods (lasting seconds). Both forms of LPP frequency filtering are influenced by presynaptic, as opposed to postsynaptic, processes; this contrasts with other hippocampal synapses. LPP frequency filtering is modified by the unique presynaptic long-term potentiation at this synapse. Computational simulations indicate that presynaptic factors associated with release probability and vesicle recycling may underlie the potent LPP-DG frequency filtering.
Subject(s)
Calcium , Perforant Pathway , Animals , Dentate Gyrus/physiology , Electric Stimulation , Entorhinal Cortex/physiology , Hippocampus/physiology , Long-Term Potentiation/physiology , Mice , Perforant Pathway/physiology , Synapses/physiologyABSTRACT
BACKGROUND: Due to safety signals after vaccination with COVID-19 vector vaccines, several states recommended to complete the primary immunization series in individuals having received one dose of ChAdOx1 (AstraZeneca) with an mRNA vaccine. However, data on safety and reactogenicity of this heterologous regimen are still scarce. The aim of this study was therefore to compare the reactogenicity and the frequency of medical consultations after boost vaccination in a heterologous regimen with ChAdOx1 and mRNA-vaccines (BNT162b2, BioNTech/Pfizer or mRNA-1273, Moderna) to homologous regimens with ChAdOx1 or mRNA-vaccines, respectively. METHODS: In an observational cohort study reactogenicity and safety were assessed 14-19 days (short-term) and 40 to 56 days (long-term) after the boost vaccination using web-based surveys. In the short-term survey solicited and unsolicited reactions were assessed, while the long-term survey focussed on health problems leading to medical consultation after the vaccination, including those that were not suspected to be vaccine-related. RESULTS: In total, 9146 participants completed at least one of the surveys (ChAdOx1/ChAdOx1: n = 552, ChAdOx1/mRNA: n = 2382, mRNA/mRNA: n = 6212). In the short-term survey, 86% with ChAdOx1/mRNA regimen reported at least one reaction, in the ChAdOx1/ChAdOx1 and mRNA/mRNA cohorts 58% and 76%, respectively (age and sex adjusted p < 0.0001). In the long-term survey, comparable proportions of individuals reported medical consultation (ChAdOx1/ChAdOx1 vs. ChAdOx1/mRNA vs. mRNA/mRNA: 15% vs. 18% vs. 16%, age and sex adjusted p = 0.398). Female gender was associated with a higher reactogenicity and more medical consultations. Younger age was associated with a higher reactogenicity, whereas elderly people reported more medical consultations. CONCLUSION: Although the short-term reactogenicity was higher with the heterologous regimen than with the homologous regimens, other factors such as higher efficacy and limited resources during the pandemic may prevail in recommending specific regimens.
Subject(s)
BNT162 Vaccine , COVID-19 , Aged , COVID-19/prevention & control , Cohort Studies , Female , Humans , RNA, Messenger/genetics , Vaccination/adverse effects , Vaccination/methods , Vaccines, Synthetic , mRNA VaccinesABSTRACT
Multiple studies indicate that adult male rodents perform better than females on spatial problems and have a lower threshold for long-term potentiation (LTP) of hippocampal CA3-to-CA1 synapses. We report here that, in rodents, prepubescent females rapidly encode spatial information and express low-threshold LTP, whereas age-matched males do not. The loss of low-threshold LTP across female puberty was associated with three inter-related changes: increased densities of α5 subunit-containing GABAARs at inhibitory synapses, greater shunting of burst responses used to induce LTP and a reduction of NMDAR-mediated synaptic responses. A negative allosteric modulator of α5-GABAARs increased burst responses to a greater degree in adult than in juvenile females and markedly enhanced both LTP and spatial memory in adults. The reasons for the gain of functions with male puberty do not involve these mechanisms. In all, puberty has opposite consequences for plasticity in the two sexes, albeit through different routes.
Subject(s)
Long-Term Potentiation , Rodentia , Animals , Female , Hippocampus/physiology , Long-Term Potentiation/physiology , Male , Spatial Memory , Synapses/physiology , gamma-Aminobutyric AcidABSTRACT
OBJECTIVE: The anti-α4ß7 integrin antibody vedolizumab is administered at a fixed dose for the treatment of IBDs. This leads to a wide range of serum concentrations in patients and previous studies had suggested that highest exposure levels are associated with suboptimal clinical response. We aimed to determine the mechanisms underlying these non-linear exposure-efficacy characteristics of vedolizumab. DESIGN: We characterised over 500 samples from more than 300 subjects. We studied the binding of vedolizumab to T cells and investigated the functional consequences for dynamic adhesion, transmigration, gut homing and free binding sites in vivo. Employing single-cell RNA sequencing, we characterised α4ß7 integrin-expressing T cell populations 'resistant' to vedolizumab and validated our findings in vitro and in samples from vedolizumab-treated patients with IBD. We also correlated our findings with a post-hoc analysis of the Gemini II and III studies. RESULTS: Regulatory T (TReg) cells exhibited a right-shifted vedolizumab binding profile compared with effector T (TEff) cells. Consistently, in a certain concentration range, the residual adhesion, transmigration, homing of and availability of functional α4ß7 on TReg cells in vivo was higher than that of/on TEff cells. We identified a vedolizumab-'resistant' α4ß7-expressing ß1+PI16+ TReg cell subset with pronounced regulatory properties as the substrate for this effect. Our observations correlated with exposure-efficacy data from Gemini II and III trials. CONCLUSION: Completely blocking TEff cell trafficking with vedolizumab, while simultaneously permitting residual homing of powerful TReg cells in an optimal 'therapeutic window' based on target exposure levels might be a strategy to optimise treatment outcomes in patients with IBD.
Subject(s)
Gastrointestinal Agents , Inflammatory Bowel Diseases , Antibodies, Monoclonal, Humanized , Carrier Proteins , Gastrointestinal Agents/pharmacology , Gastrointestinal Agents/therapeutic use , Glycoproteins/metabolism , Glycoproteins/therapeutic use , Humans , Inflammatory Bowel Diseases/drug therapy , Integrins , T-Lymphocytes, Regulatory/metabolismABSTRACT
BACKGROUND: Post carotid blood pressure fluctuation and hypertension (PEH) are associated with increased risk for adverse outcome; there is limited evidence on the impact of eversion endarterectomy (E-CEA) versus conventional endarterectomy with patch closure (C-CEA) on postoperative blood pressure course. PATIENTS AND METHODS: In this retrospective observational study, 859 consecutive carotid endarterectomy procedures between 2004 and 2014 (C-CEA n = 585 vs. E-CEA n = 274), were evaluated. Pre- and postoperative blood pressure values were recorded from recovery room until third postoperative day and compared between both techniques; influences on the dichotomous target variable "at least one postoperative blood pressure peak", that is need for postoperative vasodilators, were analyzed by a logistic regression model. Influences on postoperative systolic blood pressure were evaluated by a linear mixed effects regression model. RESULTS: Preoperative baseline blood pressure was not different between both comparison groups. During postoperative course, significantly increased mean systolic blood pressure values in the E-CEA group from recovery room to second postoperative day (recovery room C-CEA: 129.2 mm Hg vs. E-CEA: 136.5 mm Hg; P < 0.001; first postoperative day C-CEA: 132.4 mm Hg vs. E-CEA: 139.3 mm Hg; P = 0.0002; second postoperative day C-CEA: 138.6 mm Hg vs. E-CEA: 143.1 mm Hg; P = 0.023) were observed. No hyperperfusion syndrome was detected as wells as no difference in postoperative complication rate. Frequency of antihypertensive interventions was also elevated in E-CEA group (C-CEA 22.1 % vs. E-CEA 31.8 %; P = 0.003). E-CEA (OR 1.591, 95% CI [1.146; 2.202]; P = 0.005) and presence of preoperatively elevated systolic readings (OR 1.015, 95%CI [1.006;1.024]; P < 0.001) was also associated with increased need for antihypertensive interventions. CONCLUSION: E-CEA was associated with significantly elevated postoperative blood pressure, compared to C-CEA. C-CEA was associated with postoperative blood pressure decrease; however, no difference as to neurologic and surgical complications was detected between both surgical techniques in clinical practice.
Subject(s)
Blood Pressure , Endarterectomy, Carotid/methods , Hypertension/etiology , Postoperative Complications/etiology , Aged , Antihypertensive Agents/therapeutic use , Blood Pressure Determination , Endarterectomy, Carotid/adverse effects , Female , Humans , Hypertension/drug therapy , Linear Models , Male , Middle Aged , Retrospective StudiesABSTRACT
There is evidence that cannabis use during adolescence leads to memory and cognitive problems in young adulthood but little is known about effects of early life cannabis exposure on synaptic operations that are critical for encoding and organizing information. We report here that a 14-day course of daily Δ9-tetrahydrocannabinol treatments administered to adolescent rats and mice (aTHC) leads to profound but selective deficits in synaptic plasticity in two axonal systems in female, and to lesser extent male, hippocampus as assessed in adulthood. Adolescent-THC exposure did not alter basic synaptic transmission (input/output curves) and had only modest effects on frequency facilitation. Nevertheless, aTHC severely impaired the endocannabinoid-dependent long-term potentiation in the lateral perforant path in females of both species, and in male mice; this was reliably associated with impaired acquisition of a component of episodic memory that depends on lateral perforant path function. Potentiation in the Schaffer-commissural (S-C) projection to field CA1 was disrupted by aTHC treatment in females only and this was associated with both a deficit in estrogen effects on S-C synaptic responses and impairments to CA1-dependent spatial (object location) memory. In all the results demonstrate sexually dimorphic and projection system-specific effects of aTHC exposure that could underlie discrete effects of early life cannabinoid usage on adult cognitive function. Moreover they suggest that some of the enduring, sexually dimorphic effects of cannabis use reflect changes in synaptic estrogen action.
Subject(s)
Dronabinol , Memory, Episodic , Animals , Dronabinol/pharmacology , Female , Hippocampus , Long-Term Potentiation/physiology , Male , Mice , Neuronal Plasticity , Rats , Rodentia , Synaptic TransmissionABSTRACT
BACKGROUND: Experimental data have shown that the developing brain is especially vulnerable to exogenous noxious substances. The potential effects of anesthetic drugs on brain growth and development are a matter of concern. Clinical studies of children who underwent general anesthesia in their earliest years can make a major contribution to our understanding of the effects of anesthetic drugs on infants and toddlers (i.e., children under age 5). METHODS: Children born at term during the years 2007-2011 who were exposed to general anesthesia before their third birthday were included in the study. Data on general anesthesia were retrospectively evaluated, and the overall intelligence quotient (IQ) was determined prospectively as the primary target parameter. Children who had not been exposed to general anesthesia were recruited as a control group. The non-inferiority threshold was set at a difference of 5 IQ points out of a consideration of clinical relevance. RESULTS: 430 complete data sets were available from exposed children and 67 from members of the control group. The exposed group achieved a mean IQ score of 108.2, with a 95% confidence interval of [107; 109.4]; the corresponding values in the control group were 113 [110; 116.1]. Both groups achieved a mean score that was higher than the expected 100 points. After adjustment for age, socioeconomic status, and sex, the difference between the two groups was 2.9 points [0.2; 5.6], indicating a significantly better outcome in the control group than in the exposed group. The non-inferiority threshold of 5 IQ points was within the confidence interval; thus, non-inferiority was not demonstrated. CONCLUSION: The fact that both groups achieved a higher IQ score than the expected 100 points may be attributable, at least in part, to the restriction of the study to children born at term. The results indicate that general anesthesia in early childhood is not associated with markedly reduced intelligence in later years, although noninferiority could not be demonstrated.
Subject(s)
Anesthesia, General , Intelligence , Anesthesia, General/adverse effects , Child, Preschool , Humans , Infant , Infant, Newborn , Intelligence Tests , Retrospective Studies , Social ClassABSTRACT
Synaptic disturbances in excitatory to inhibitory (E/I) balance in forebrain circuits are thought to contribute to the progression of Alzheimer's disease (AD) and dementia, although direct evidence for such imbalance in humans is lacking. We assessed anatomical and electrophysiological synaptic E/I ratios in post-mortem parietal cortex samples from middle-aged individuals with AD (early-onset) or Down syndrome (DS) by fluorescence deconvolution tomography and microtransplantation of synaptic membranes. Both approaches revealed significantly elevated E/I ratios for AD, but not DS, versus controls. Gene expression studies in an independent AD cohort also demonstrated elevated E/I ratios in individuals with AD as compared to controls. These findings provide evidence of a marked pro-excitatory perturbation of synaptic E/I balance in AD parietal cortex, a region within the default mode network that is overly active in the disorder, and support the hypothesis that E/I imbalances disrupt cognition-related shifts in cortical activity which contribute to the intellectual decline in AD.
Subject(s)
Alzheimer Disease/physiopathology , Cognitive Dysfunction/physiopathology , Down Syndrome/physiopathology , Parietal Lobe/anatomy & histology , Parietal Lobe/metabolism , Synapses/metabolism , Synaptic Membranes/physiology , Amyloid beta-Peptides/metabolism , Animals , Anura , Autopsy , Cognitive Dysfunction/metabolism , Disks Large Homolog 4 Protein/metabolism , Down Syndrome/metabolism , Female , GABA Plasma Membrane Transport Proteins/genetics , GABA Plasma Membrane Transport Proteins/metabolism , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Humans , Male , Membrane Proteins/metabolism , Middle Aged , Nerve Net/physiopathology , Oocytes/physiology , Parietal Lobe/physiopathology , Synapses/pathology , Synaptic Membranes/metabolism , Synaptosomes/metabolism , Synaptosomes/pathology , Tomography, Optical , Transcriptome/geneticsABSTRACT
Evidence suggests encoding of recent episodic experiences may be enhanced by a subsequent salient event. We tested this hypothesis by giving rats a 3-min unsupervised experience with four odors and measuring retention after different delays. Animals recognized that a novel element had been introduced to the odor set at 24 but not 48 h. However, when odor sampling was followed within 5 min by salient light flashes or bedding odor, the memory lasted a full 2 d. These results describe a retroactive influence of salience to promote storage of episodic information and introduce a unique model for studying underlying plasticity mechanisms.