Search

Mark Vogt,1 Dennis J van Gerwen,2 John J van den Dobbelsteen,2 Martin Hagenaars,3 1Department of Anesthesiology, Erasmus MC Sophia Children Hospital, Rotterdam, the Netherlands; 2Department of Biomechanical Engineering, Delft University of Technology, Delft, the Netherlands; 3Department of Anesthesiology, Canisius Wilhelmina Ziekenhuis, Nijmegen, the Netherlands Abstract: Performance of neuraxial blockade using a midline approach can be technically difficult. It is therefore important to optimize factors that are under the influence of the clinician performing the procedure. One of these factors might be the chosen point of insertion of the needle. Surprisingly few data exist on where between the tips of two adjacent spinous processes the needle should be introduced. A geometrical model was adopted to gain more insight into this issue. Spinous processes were represented by parallelograms. The length, the steepness relative to the skin, and the distance between the parallelograms were varied. The influence of the chosen point of insertion of the needle on the range of angles at which the epidural and subarachnoid space could be reached was studied. The optimal point of insertion was defined as the point where this range is the widest. The geometrical model clearly demonstrated, that the range of angles at which the epidural or subarachnoid space can be reached, is dependent on the point of insertion between the tips of the adjacent spinous processes. The steeper the spinous processes run, the more cranial the point of insertion should be. Assuming that the model is representative for patients, the performance of neuraxial blockade using a midline approach might be improved by choosing the optimal point of insertion. Keywords: neuraxial blockade, midline approach, optimal point of insertion, geometrical model

Exposure therapy consists of exposing patients to their fears and thereby diminishing their harm expectancies (i.e., extinction or expectancy learning). Although effective for many anxiety patients, its long-term success depends on the generalization of these harm expectancies to other stimuli. However, research shows that this generalization of extinction is limited. Besides decreasing harm expectancies, fear reduction may also be achieved by changing the meaning of an aversive memory representation (US revaluation). Imagery rescripting (ImRs) may be more successful in generalizing fear reduction because it allegedly works through US revaluation. The current experiment aimed to test working mechanisms for ImRs and extinction (revaluation and expectancy learning, respectively), and to examine generalization of fear reduction. In a fear conditioning paradigm, 113 healthy participants watched an aversive film clip that was used as the US. The manipulation consisted of imagining a script with a positive ending to the film clip (ImRs-only), extinction (extinction-only), or both (ImRs + extinction). Results showed enhanced US revaluation in ImRs + extinction. US expectancy decreased more strongly in the extinction conditions. Generalization of fear reduction was found in all conditions. Our results suggest different working mechanisms for ImRs and exposure. Future research should replicate this in (sub)clinical samples., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Introduction: We systematically describe the morphology and accessibility of interspinous spaces across age groups of patients. Our primary goal was to objectively estimate if the maneuver space for a virtual spinal needle changes with age. Our secondary goal was to estimate if the optimal site and angle for midline neuraxial puncture change with age., Methods: Measurements were performed in mid-sagittal CT images. The CT images were retrospectively collected from the database of the Department of Radiology of our hospital. Three age groups were studied: 21-30 years (n=36, abbreviated Y(oung)), 51-60 years (n=43, abbreviated M(iddle-aged)) and older than 80 years (n=46, abbreviated Old).A needle trajectory is defined by the chosen puncture point and by the angle at which the needle is directed to its target. We define a Spinal Accessibility Index (SAI) by numerically integrating for an interspace all possible combinations of puncture points and angles that lead to a successful virtual puncture. Successful in this context means that the needle tip reaches the spinal or epidural space without bone contact. Reproducible calculation of the SAI was performed with the help of custom-made software. The larger the value of the SAI, the more possible successful needle trajectories exist that the practitioner may choose from.The optimal puncture point and optimal angle in an age group at a certain level of the spine are defined by the combination of these two, which generates the highest success rate of the entire sample of this age group., Results: At all levels of the spine, the median SAI differed significantly between age groups (independent-samples Kruskal-Wallis test, p<0.001-0.047). The SAI consistently decreased with increasing age. Post-hoc analyses using pairwise comparisons showed a significantly higher SAI in group Y versus Old at all levels (p<0.001-0.006) except at level thoracic (Th)1-Th2 (p=0.138). The SAI was significantly higher in group M versus Old at all levels (p<0.001-0.028) except at level Th1-Th2 (p=0.061), Th4-Th5 (p=0.083), Th9-Th10 (p=1.00) and Th10-Th11 (p=1.00)., Conclusions: Needle maneuver space in midline neuraxial puncture significantly decreases with progressive age at all levels of the spine. Optimal puncture points and angles are similar between age groups., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Non-rapid eye movement (NREM) parasomnias are often benign and transient, requiring no formal treatment. However, parasomnias can also be chronic, disrupt sleep quality, and pose a significant risk of harm to the patient or others. Numerous behavioral strategies have been described for the management of NREM parasomnias, but there have been no published comprehensive reviews. This systematic review was conducted to summarize the range of behavioral and psychological interventions and their efficacy., Methods: We conducted a systematic search of the literature to identify all reports of behavioral and psychological treatments for NREM parasomnias (confusional arousals, sexsomnia, sleepwalking, sleep terrors, sleep-related eating disorder, parasomnia overlap disorder). This review was conducted in line with PRISMA guidelines. The protocol was registered with PROSPERO (CRD42021230360). The search was conducted in the following databases (initially on March 10, 2021 and updated February 24, 2023): Ovid (MEDLINE), Cochrane Library databases (Wiley), CINAHL (EBSCO), PsycINFO (EBSCO), and Web of Science (Clarivate). Given a lack of standardized quantitative outcome measures, a narrative synthesis approach was used. Risk of bias assessment used tools from Joanna Briggs Institute., Results: A total of 72 publications in four languages were included, most of which were case reports (68%) or case series (21%). Children were included in 32 publications and adults in 44. The most common treatment was hypnosis (33 publications) followed by various types of psychotherapy (31), sleep hygiene (19), education/reassurance (15), relaxation (10), scheduled awakenings (9), sleep extension/scheduled naps (9), and mindfulness (5). Study designs and inconsistent outcome measures limited the evidence for specific treatments, but some evidence supports multicomponent CBT, sleep hygiene, scheduled awakenings, and hypnosis., Conclusions: This review highlights the wide breadth of behavioral and psychological interventions for managing NREM parasomnias. Evidence for the efficacy of these treatments is limited by the retrospective and uncontrolled nature of most research as well as the infrequent use of validated quantitative outcome measures. Behavioral and psychological treatments have been studied alone and in various combinations, and recent publications suggest a trend toward preference for multicomponent cognitive behavioral therapies designed to specifically target priming and precipitating factors of NREM parasomnias., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: The Public Health Services in the Rotterdam region, the Netherlands, observed a substantial decrease of non-COVID-19 notifiable infectious diseases and institutional outbreaks during the first wave of the COVID-19 epidemic. We describe this change from mid-March to mid-October 2020 by comparing with the pre-COVID-19 situation., Methods: All cases of notifiable diseases and institutional outbreaks reported to the Public Health Services Rotterdam-Rijnmond between 1st January and mid-October 2020 were included. Seven-day moving averages and cumulative cases were plotted against time and compared to those of 2017-2019. Additionally, Google mobility transit data of the region were plotted, as proxy for social distancing., Results: Respiratory, gastrointestinal, and travel-related notifiable diseases were reported 65% less often during the first wave of the COVID-19 epidemic than in the same weeks in 2017-2019. Reports of institutional outbreaks were also lower after the initially imposed social distancing measures; however, the numbers rebounded when measures were partially lifted., Conclusions: Interpersonal distancing and hygiene measures imposed nationally against COVID-19 were in place between mid-March and mid-October, which most likely reduced transmission of other infectious diseases, and may thus have resulted in lower notifications of infectious diseases and outbreaks. This phenomenon opens future study options considering the effect of local outbreak control measures on a wide range of non-COVID-19 diseases. Targeted, tailored, appropriate and acceptable hygiene and distancing measures, specifically for vulnerable groups and institutions, should be devised and their effect investigated., (© 2022. The Author(s).)

Tonic immobility (TI; state of motor inhibition during threat) has been implicated in the onset of intrusive trauma memories, while controllability was associated with reduced anxiety. The present study investigated the interaction between TI and control in the development of intrusive memories of an analogue trauma. Sixty-four participants watched negative pictures while being allowed to close their eyes (InControl) or not (NoControl). They completed measures for spontaneous TI afterwards and recorded intrusive memories of the pictures in a diary in the subsequent week. Bayesian analyses were used to test informative hypotheses. Spontaneous TI during picture viewing was positively associated with increased intrusion frequency. Intrusion frequency did not differ for InControl versus NoControl. Moderation (control x TI) and non-moderation (main effect of TI only) were both adequate models, with no preference. Our results confirm the importance of TI in PTSD development. Implications of the findings regarding control merit more research.

Background: Low spontaneous EEG theta/beta ratio (TBR) is associated with greater executive control. Their role in regulation of attentional bias for stimuli of different threat-levels is unknown., Objectives: To provide the first relations between frontal TBR, trait anxiety and attentional bias to mildly and highly threatening stimuli at different processing-stages., Methods: Seventy-four healthy volunteers completed spontaneous EEG measurement, a self-report trait anxiety questionnaire and a dot-probe task with stimuli of different threat-level and 200 and 500 ms cue-target delays., Results: Participants with high TBR directed attention towards mildly threatening and avoided highly threatening pictures. Moreover, the most resilient participants, (low TBR and low trait anxiety) showed attention towards highly threatening stimuli. There were no effects of delay., Conclusions: These data confirm that executive control is crucial for the study of threat-related attentional bias and further support the notion that TBR is a marker of cognitive control over emotional information., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objectives: Neuraxial blockade using a midline approach can be challenging. Part of this challenge lies in finding the optimal approach of the needle to its target. The present study aimed at finding (1) the optimal point of insertion of the needle between the tips of 2 adjacent spinous processes and (2) the optimal angle relative to the skin at which the needle should approach the epidural or subarachnoid space., Methods: A computer algorithm systematically analyzed computed tomography scans of vertebral columns of a cohort of 52 patients. On midsagittal sections, the possible points of insertion of a virtual needle and the corresponding angles through which the epidural or subarachnoid space can be reached were calculated., Results: The point chosen to introduce the needle between 2 adjacent spinous processes determines the range of angles through which the epidural or subarachnoid space can be reached. At the thoracic interspaces 1-2 through 3-4, thoracic interspaces 5-6 through 9-10, and at the lumbar vertebral interspaces 2-3 through 4-5, the optimal point of insertion is slightly inferior to the point halfway between the tips of the spinous processes. For thoracic interspace 4-5, the optimal point of insertion is slightly superior to the point halfway between the tips of the spinous processes. For the other interspaces, the optimal point of insertion is approximately halfway between the tips of the spinous processes. The optimal angle to direct the needle varies from 9 degrees at the thoracolumbar junction and at the lumbar interspaces 3-4 and 4-5, to 53 degrees at the thoracic interspace 7-8., Conclusions: Our study has resulted in practical suggestions-based on accurate, reproducible measurements in patients-as to where to insert the needle and how to angulate the needle when performing neuraxial anesthesia using a midline approach.

A 72-year-old man presented to the emergency clinic with motor restlessness and diminished consciousness 24 hours after he had mistakenly been given venlafaxine. He was referred from the psychiatric clinic where he was treated with tranylcypromine. Shortly after arrival, a severe serotonin syndrome developed with generalised myoclonic seizures, hyperreflexia, hypertonia, a rapid increase in temperature to 40.9 degrees C, hypertension, tachycardia, respiratory insufficiency, hyperkalaemia and metabolic acidosis. The patient was treated with the sedative propofol and the muscle relaxant rocuronium, followed by intubation and artificial respiration. He was cooled on a cooling mattress. Twenty-four hours later the airway tube could be removed and after 48 hours he was returned to the psychiatric ward in good condition. Tranylcypromine is a monoamine oxidase inhibitor and venlafaxine is a serotonin and noradrenaline reuptake inhibitor. When two serotoninergic agents are combined, the serotonin syndrome may develop, and this may be life-threatening. The treatment of this syndrome with propofol and rocuronium can be given quickly and safely in practically every hospital.

Improved (n = 21) and nonimproved (n = 13) PTSD patients (a mixed trauma population) were compared for fear activation and habituation patterns during and between the 1st and 2nd prolonged exposure sessions. Drop-outs (n = 11) were also evaluated. Nonimproved patients had significantly higher ratings of anxiety at the start of the first exposure session. Improved patients showed more within-session habituation during the self-exposures at home and more between-session habituation. Even after controlling for initial PTSD and depression symptom severity, habituation between the first and second exposure sessions was significantly related to treatment outcome. Patients who dropped out of the treatment were found not to differ from completers on fear activation and within-session habituation during the first exposure session.

This article reviews our immunotherapy research with natural killer (NK) cells in a syngeneic rat colorectal cancer liver and lung metastasis model. Using adoptive transfer of interleukin (IL)-2-activated NK cells, NK cells were shown to selectively infiltrate the tumors. More NK cells were found in tumors when the NK cells were directly injected into tumor-draining blood vessels than when the cells were injected in systemic blood vessels. Under optimal conditions, a limited, though significant, effect of adoptively transferred NK cells on tumor growth was shown. We observed that both endogenous and adoptively transferred NK cells were predominantly present in the stroma surrounding the tumor cell nodules. It is possible that they did not penetrate the nodules containing the tumor cells because of the presence of a basal membrane-like structure around these nodules. Adoptively transferred NK cells may initiate elimination of tumor cells by activating other effector cells, whereas some may eliminate tumor cells by direct cell-cell contact. A diverse array of molecules was shown to be involved in this process. CD45 on NK cells was found to be important in initiating the lysis-inhibitory signal upon binding of 'self' major histocompatibility complex (MHC) class I on potential target cells. Our results indicate that NK-cell cancer therapy is still promising and needs improvement.

In this article we report about the role that tumor structure and extracellular matrix (ECM) may play in immunotherapy and in gene therapy using adenoviruses. We performed studies in a rat model for colorectal cancer, CC531, and in specimens of human colorectal cancer. The tumors were composed of two compartments, tumor cell nests surrounded by stromal cells. ECM proteins were expressed in the stromal part, where the blood vessels were also located. Furthermore, in several tumors, the tumor cell nests were surrounded by basal membrane-like structures. Therefore, in vascular approaches to treat cancer, therapeutic agents on their route to tumor cells may be hampered by ECM to reach tumor cells. We found that immune cells were abundantly present in tumors from colorectal origin. These cells were, however, not found in direct contact with tumor cells, but mainly in the stromal part of the tumor. Adenoviruses, when intravascularly injected, did not reach tumor cells in the CC531 rat model. Tumor cells were only infected, and even then in limited numbers, in cases of intratumoral injection. We hypothesize that ECM in a tumor is a barrier both for immune cells and for adenoviruses to make direct contact with these tumor cells, and thus limits colorectal tumor therapy.

Cytotoxicity and production of cytokines are two important functions of NK cells. These two different NK functions were studied in a syngeneic rat model in relation to MHC class I expression. We focussed on the mechanism by which NK cells modulate MHC class I expression on target cells and how this interferes with NK cell-mediated lysis. Using transfection experiments an inhibitory role on NK cell cytotoxicity for expression of target cells of RT1.A, rat MHC class I, was found. Co-culturing syngeneic tumor cells and NK cells resulted in enhanced MHC class I expression on the surviving tumor cell fraction, which was less susceptible to NK lysis. Increased tumor cell MHC class I was due to production of a soluble factor by NK cells, most likely interferon gamma. The regulatory function of NK cells shows here, that the enhancing of MHC class I expression on tumor cells in vitro and in vivo, results in downregulation of their target cell killing, but at the same time may facilitate the cytotoxic T cell function.

In this paper we describe 4 new monoclonal antibodies to be applied in rat models for cancer. The monoclonal antibodies were obtained by immunizing Balb/c mice with CC531 rat colon adenocarcinoma cells. Hybridomas were produced and 4 were selected for their reactivity with CC531 in vitro (MG1, 2, 3 and 4). All 4 antibodies recognized other rat tumour cell lines and showed limited cross-reactivity with normal rat tissues. Intraperitoneally injected MG1, 2 and 4 homed to in vivo growing, artificially induced CC531 liver metastases. In these in vivo experiments, limited cross-reactivity with normal rat tissues, predominantly of the gastro-intestinal tract, was found. MG4 was found to enhance lysis of CC531 tumour cells mediated by IL-2 activated, cultured natural killer cells. These antibodies are potentially useful for antibody-based laboratory techniques and for investigation of antibody-based immunotherapy of cancer in a rat model.

The colon adenocarcinoma cell line CC531 was adopted as a model for immunotherapeutical treatment of experimental colorectal metastases in a syngeneic rat model. We studied the presence and localization of T and natural killer cells, vessels and matrix proteins in in vivo growing CC531 tumours by immunohistochemistry. CC531 tumours were induced either in the lungs by injecting CC531 tumour cells into a tail vein or in the liver by injection of CC531 tumour cells under the liver capsule or into a mesenteric vein. All 3 tumour types were composed of islets of tightly apposed tumour cells surrounded by abundantly present tumour-stroma which contained tumour vessels and matrix proteins. Some of these matrix proteins, especially laminin and collagen IV formed a basal membrane-like structure around the tumour nodules. This structure was most pronounced in mesenteric vein-induced liver tumours and less prominent in subcapsular-induced liver tumours and tail vein-induced lung tumours. Tumour-infiltrating lymphocytes of both T and natural killer cell origin were found in the tumours, but predominantly in the tumour stroma, separated from the islets of tumour cells by the basal membrane-like structure. We hypothesize that the matrix proteins of these tumours play an ambivalent role: they may provide a substratum for migration of effector cells into the tumour stroma but may also provide a barrier preventing direct contact between tumour target cells and immune effector cells.

Previous experiments in a syngeneic rat liver tumor model using the colon adenocarcinoma CC531 demonstrated that injection of interleukin-2 (IL-2) induced significant antitumor responses. Furthermore, it was found that this treatment strategy was accompanied by an increase in the number of natural killer (NK) cells in and around the tumor. In the present study, the role of endogenous NK cells in IL-2-mediated antitumor responses was further elucidated by depleting tumor-bearing rats of NK cells, using the anti-CD161A mouse IgG1 antibody 3.2.3. Rats were depleted either after or prior to tumor induction and subsequently treated with IL-2. The results demonstrated that depletion of NK cells in tumor-bearing rats did not influence IL-2-induced antitumor effects. In addition, injection of IL-2 in NK-cell-depleted rats induced repopulation of NK cells in the peripheral blood from 3 days on and further after the last injection with IL-2. Therefore, the possibility cannot be excluded that de novo recruited NK cells play a role in attaining IL-2 mediated antitumor effects, but NK cells, which were present before or during the start of IL-2 therapy, were not relevant.

CaMBr1 is a blood group-related tumour-associated antigen, whose pattern of expression provides a therapeutic window for passive or active immunotherapy and points to the promise of a vaccine against carcinomas overexpressing this antigen. In this context, an animal model that closely mimics the human situation would be extremely useful. We, therefore, utilised the murine monoclonal antibody MBr1, which defines CaMBr1, as a useful probe to detect the molecule targeted for vaccine development on canine and feline spontaneous breast and uterus tumours and on their normal counterparts, and on rat normal tissues and carcinoma cell lines. Immunoperoxidase staining of cryostat sections revealed homogeneous CaMBr1 expression only in normal feline uterus and a uterus papilloma, whereas MBr1 reactivity was very weak and heterogeneous in normal (1/3 and 1/3) and tumour (1/10 and 1/6) breast tissues from dogs and cats, respectively. In contrast, the data obtained in rat tissues were reproducible in the strains tested and showed that CaMBr1 was expressed in all epithelial tissues of the digestive tract, although with variable intensities. Monoclonal antibody staining appeared to correspond to membrane-bound structures as well as mucinous secretions. Similarly, secretion products of lactating mammary glands expressed CaMBr1. The spectrum of expression on rat digestive tract was broader than that in humans but the specificity of MBr1 reactivity was confirmed by competition assay with a synthetic tetrasaccharide that mimics the CaMBr1 antigen. On FACS analysis, only one of two clonal derivatives of the rat breast carcinoma line RAMA 25 expressed CaMBr1, and a negative cell subset was evident in repeated experiments. By contrast, both colon carcinoma lines, DHD/K12 and CC531, showed staining with MBr1, albeit at different levels of intensity, and no evidence of a negative subset. The cell line CC531 maintained or even increased CaMBr1 expression levels following transplantation in syngeneic immunocompetent animals. Our data suggest the usefulness of the rat as a test model for vaccines against human cancers overexpressing the CaMBr1 antigen.

Bispecific monoclonal antibodies (BiMAb) have been shown to be able to contribute to an immunological approach in cancer therapy. In this review, essential aspects regarding the production of BiMAb and modes to apply them in immunotherapy for cancer are discussed. The pros and cons of BiMAb are considered, and the development from application in animal models to clinical studies is reviewed. The most important clinical trials are summarized, and the different problems encountered are discussed. Provided some crucial problems can be overcome, BiMAb will have a place in the treatment of cancer, especially in the setting of minimal residual disease.