| 1. |
- Björk Wilhelms, Daniel, et al.
(författare)
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Cyclooxygenase isoform exchange blocks inflammatory symptoms
- 2014
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cyclooxygenase‐2 (COX‐2) is the main source of inducible prostaglandin E2 production and mediates inflammatory symptoms including fever, loss of appetite and hyperalgesia. In contrast, COX‐1 is dispensable for most inflammatory symptoms. Global deletion of COX‐2 leads to a blockade of inflammation‐induced fever and appetite loss but also to high rates of fetal mortality. The latter is unfortunate since mice without COX‐2 are powerful tools in the study of inflammation and cardiovascular medicine. The differential functionality of the COX isoforms could be due to differences in regulatory regions of the genes, leading to different expression patterns, or to differences in the coding sequence, leading to distinct functional properties of the proteins. To study this in the context of inflammatory symptoms, we used mice in which the coding sequence of COX‐2 was replaced by the corresponding sequence of COX‐1. In these mice, COX‐1 mRNA was induced by inflammation but COX‐1 protein expression did not fully mimic inflammation‐induced COX‐2 expression. Just like mice globally lacking COX‐2, these mice showed a complete lack of fever and inflammation‐induced anorexia. However, as previously reported, they displayed close to normal survival rates. This shows that the COX activity generated from the hybrid gene was strong enough to allow survival but not strong enough to mediate inflammatory symptoms, making the line an interesting alternative to COX‐2 knockouts for the study of inflammation. Our results also show that the functional differences between COX‐1 and COX‐2 in the context of inflammatory symptoms is not only dependent on the features of the promoter regions. Instead they indicate that there are fundamental differences between the isoforms at translational or posttranslational levels, which make hybrid genes less functional.
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| 2. |
- Björk Wilhelms, Daniel
(författare)
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Fever : Role of brain endothelial prostaglandins
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fever and loss of appetite are two of the most fundamental manifestations of disease. These disease symptoms, which lead to deviations from normal body temperature and food intake patterns, are seen in a vast array of infectious and inflammatory conditions. It is known that peripheral signals from the immune system are essential triggers for these responses, which are orchestrated by neuronal circuits in the brain. Due to the blood‐brain barrier, peripheral inflammatory signals require a specific mode of transmission into the brain. Such mechanisms have been proposed, but interventional studies of these mechanisms have never rendered conclusive results. In this thesis, we present the first functional evidence of cyclooxygenase 2 (COX‐2) and microsomal prostaglandin E synthase type 1 (mPGES‐1) mediated prostaglandin E2 synthesis in the blood‐brain barrier endothelial cells as a signaling mechanism in the initiation of inflammatory fever. We also show that one of the world’s most widely used antipyretics, paracetamol, acts by inhibition of COX‐2. Combined with the finding that COX‐2 and mPGES‐1 in brain endothelial cells play a key role in inflammatory fever, this finding suggests that paracetamol inhibits fever by specifically blocking prostaglandin E2 synthesis in blood‐brain barrier endothelium. In another symptom of inflammation, anorexia, the cellular origin of peripheral signals triggering acute anorexia are largely unknown. We show that the expression of myeloid differentiation primary response gene 88 (Myd88) in myeloid cells is important for the initiation of acute inflammatory anorexia and the maintenance of cancer anorexia‐cachexia.Taken together, these findings provide a significant advancement of our understanding of the mechanisms triggering acute inflammatory fever and anorexia and also explain the antipyretic effect of paracetamol.
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| 3. |
- Brito, H. O., et al.
(författare)
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Female Sex Hormones Influence the Febrile Response Induced by Lipopolysaccharide, Cytokines and Prostaglandins but not by Interleukin-1 beta in Rats
- 2016
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Ingår i: Journal of neuroendocrinology (Print). - : Wiley-Blackwell. - 0953-8194 .- 1365-2826. ; 28:10
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Tidskriftsartikel (refereegranskat)abstract
- There are differences in the immune response, and particularly fever, between males and females. In the present study, we investigated how the febrile responses induced by lipopolysaccharide (LPS) and different endogenous pyrogens were affected by female gonadal hormones. The febrile response to i.p. injection of LPS (50g/kg) was 40% lower in female rats compared to male or ovariectomised (OVX) female rats. Accordingly, oestrogen replacement in OVX animals reduced LPS-induced fever. Treatment with the prostaglandin synthesis inhibitor indomethacin (2mg/kg, i.p. 30min before) reduced the febrile response induced by LPS in both OVX (88%) and sham-operated (71%) rats. In line with the enhanced fever in OVX rats, there was increased expression of cyclooxygenase-2 (COX-2) in the hypothalamus and elevated levels of prostaglandin E-2 (PGE(2)). In addition, OVX rats were hyper-responsive to PGE(2) injected i.c.v. By contrast to the enhanced fever in response to LPS and PGE(2), the febrile response induced by i.c.v. injection of interleukin (IL)-1 was unaffected by ovariectomy, whereas the responses induced by tumour necrosis factor (TNF)- and macrophage inflammatory protein (MIP)-1 were completely abrogated. These results suggest that the mediators involved in the febrile response in females are similar to males, although the reduction of female hormones may decrease the responsiveness of some mediators such as TNF- and MIP-1. Compensatory mechanisms may be activated in females after ovariectomy such as an augmented synthesis of COX-2 and PGE(2).
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| 4. |
- Glasin, Joakim, et al.
(författare)
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Wireless vitals : Proof of concept for wireless patient monitoring in an emergency department setting
- 2019
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Ingår i: Journal of Biophotonics. - : Wiley-VCH Verlagsgesellschaft. - 1864-063X .- 1864-0648. ; 12:4
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Tidskriftsartikel (refereegranskat)abstract
- Vital sign assessment is a common task in emergency medicine, but resources for continuous monitoring are restricted, data is often recorded manually, and entangled wires cause frustration. Therefore, we designed a small, wireless photoplethysmographic device capable of continuously assessing pulse, respiratory frequency and oxygen saturation on the sternum and tested the performance and feasibility in an emergency department setting. Fifty (56.3 20.2 years), consenting emergency patients (29 male) were recruited. Heart rate, respiratory rate and oxygen saturation were recorded simultaneously using the device and standard monitoring equipment. Data was compared using Bland-Altman plotting (heart rate, respiratory rate) and mean difference (oxygen saturation). The bias for heart- and respiratory rate was 0.4 (limits of agreements -11.3, 12.2 and -6.1, 7.0). Mean difference for oxygen saturation was -0.21 +/- 2.35%. This may be the first wireless device to use photoplethysmography on the sternum for vital sign assessment. We noted good agreement with standard monitors, but lack of standardization in data processing between monitoring systems may limit the generalizability of these findings. Although further improvements are needed, the feasibility of this approach provides proof of concept for a new paradigm of large scale, wireless patient monitoring.
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| 5. |
- Henricson, Joakim, et al.
(författare)
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Diffuse Reflectance Spectroscopy : Getting the Capillary Refill Test Under Ones Thumb
- 2017
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Ingår i: Journal of Visualized Experiments. - : MyJove Corporation. - 1940-087X. ; :130
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Tidskriftsartikel (refereegranskat)abstract
- The capillary refill test was introduced in 1947 to help estimate circulatory status in critically ill patients. Guidelines commonly state that refill should occur within 2 s after releasing 5 s of firm pressure (e.g., by the physicians finger) in the normal healthy supine patient. A slower refill time indicates poor skin perfusion, which can be caused by conditions including sepsis, blood loss, hypoperfusion, and hypothermia. Since its introduction, the clinical usefulness of the test has been debated. Advocates point out its feasibility and simplicity and claim that it can indicate changes in vascular status earlier than changes in vital signs such as heart rate. Critics, on the other hand, stress that the lack of standardization in how the test is performed and the highly subjective nature of the naked eye assessment, as well as the tests susceptibility to ambient factors, markedly lowers the clinical value. The aim of the present work is to describe in detail the course of the refill event and to suggest potentially more objective and exact endpoint values for the capillary refill test using diffuse polarization spectroscopy.
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| 6. |
- Henricson, Joakim, 1977-, et al.
(författare)
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In vivo dose-response analysis to acetylcholine : pharmacodynamic assessment by polarized reflectance spectroscopy
- 2022
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Ingår i: Scientific Reports. - London, United Kingdom : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Transdermal iontophoresis offers an in vivo alternative to the strain-gauge model for measurement of vascular function but is limited due to lack of technical solutions for outcome assessment. The aims of this study were to, after measurement by polarized reflectance spectroscopy (PRS), use pharmacodynamic dose-response analysis on responses to different concentrations of acetylcholine (ACh); and to examine the effect of three consecutively administered iontophoretic current pulses. The vascular responses in 15 healthy volunteers to iontophorised ACh (5 concentrations, range 0.0001% to 1%, three consecutive pulses of 0.02 mA for 10 min each) were recorded using PRS. Data were fitted to a four-parameter logistic dose response model and compared. Vascular responses were quantifiable by PRS. Similar pharmacodynamic dose response curves could be generated irrespectively of the ACh concentration. Linearly increasing maximum vasodilatory responses were registered with increasing concentration of ACh. A limited linear dose effect of the concentration of ACh was seen between pulses. Polarized reflectance spectroscopy is well suited for measuring vascular responses to iontophoretically administrated ACh. The results of this study support further development of iontophoresis as a method to study vascular function and pharmacological responses in vivo.
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| 7. |
- Henricson, Joakim, 1977-, et al.
(författare)
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Respiratory rate monitoring in healthy volunteers by central photoplethysmography compared to capnography
- 2022
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Ingår i: Journal of Biophotonics. - : Wiley-V C H Verlag GMBH. - 1864-063X .- 1864-0648. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Monitoring of respiration is a central task in clinical medicine, crucial to patient safety. Despite the uncontroversial role of altered respiratory frequency as an important sign of impending or manifest deterioration, reliable measurement methods are mostly lacking outside of intensive care units and operating theaters. Photoplethysmography targeting the central blood circulation in the sternum could offer accurate and inexpensive monitoring of respiration. Changes in blood flow related to the different parts of the respiratory cycle are used to identify the respiratory pattern. The aim of this observational study was to compare photoplethysmography at the sternum to standard capnography in healthy volunteers. Bland Altman analysis showed good agreement (bias -0.21, SD 1.6, 95% limits of agreement -3.4 to 2.9) in respiratory rate values. Photoplethysmography provided high-quality measurements of respiratory rate comparable to capnographic measurements. This suggests that photoplethysmography may become a precise, cost-effective alternative for respiratory monitoring.
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| 8. |
- Hörlin, Erika, 1974-, et al.
(författare)
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Inter-rater reliability of the Clinical Frailty Scale by staff members in a Swedish emergency department setting
- 2022
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Ingår i: Academic Emergency Medicine. - : Wiley. - 1069-6563 .- 1553-2712. ; 29:12, s. 1431-1437
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Tidskriftsartikel (refereegranskat)abstract
- Introduction As frailty among the elderly is receiving increasing attention in emergency departments (EDs) around the world, the use of frailty assessment tools is growing. An often used such tool is the Clinical Frailty Scale (CFS), whose inter-rater reliability has been sparingly investigated in ED settings. No inter-rater reliability study regarding CFS has previously been performed within the Scandinavian ED context. The primary aim of this study was to evaluate the inter-rater reliability of the CFS in a Swedish ED setting. Methods This was a prospective observational study conducted at three Swedish EDs. Patients >= 65 years were independently assessed with CFS by their responsible physician, registered nurse, and assistant nurse. Demographic information for each assessor was collected, along with frailty status (frail/not frail) on the basis of clinical judgment. Inter-rater reliability was calculated using intraclass correlation coefficient (ICC), whereas agreement of frailty assessed by CFS (dichotomized between frail/not frail, cutoff at >= 5 points) versus solely by clinical judgment was calculated by using cross-tabulation. Results One-hundred patients were included. We found inter-rater reliability to be moderate to good (ICC 0.78, 95% confidence interval [CI] 0.72-0.84), regardless of whether the care team included an emergency physician (ICC 0.74, 95% CI 0.62-0.83) or an intern/resident from another specialty (ICC 0.83, 95% CI 0.74-0.89). The agreement of clinically judged frailty compared to frailty according to CFS was 84%. In the opposing cases, staff tended to assess patients as frail to a higher extent using clinical judgment than by applying CFS on the same patient. Conclusions The CFS appears to have a moderate to good inter-rater reliability when used in a clinical ED setting. When guiding clinical decisions, we advise that the CFS score should be discussed within the team. Further research needs to be performed on the accuracy of clinical judgment to identify frailty in ED patients.
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| 9. |
- Ruud, Johan, et al.
(författare)
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MyD88 in hematopoietic cells, but not in cerebrovascular endothelial cells or neural cells, is critical for inflammation- and cancer-induced loss of appetite
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Loss of appetite concomitant with reduced food intake is a hallmark of both acute and chronic inflammatory diseases. Yet, despite extensive investigations, the underlying mechanisms remain undefined. Here we addressed this issue using mice lacking MyD88, critical for Tolllike and IL-1 receptor family signaling, generally or in specific cell types. Ubiquitous null deletions conferred complete resistance to bacterial lipopolysaccharide (LPS) induced anorexia, but this resistance was lost when knock-out mice subjected to whole-body irradiation to delete hematopoietic cells were transplanted with wild-type bone-marrow. In line with this observation, mice lacking MyD88 in hematopoietic cells were largely protected against LPS-induced anorexia, whereas mice with abrogated MyD88 signaling in neural cells, being leaner and smaller, developed anorexia of similar magnitude as wild-type littermates. The effect of hematopoietic MyD88-deletion on feeding seemed however partially dissociated from the effect on body weight, since LPS triggered weight loss, although attenuated, in these mutants. Furthermore, MyD88 deficiency in the cerebrovascular endothelium affected neither LPS-induced anorexia nor weight loss. In a model for the cancer anorexia-cachexia syndrome, inactivation of MyD88 in hematopoietic cells strongly impaired the anorexia development and protected against body weight loss. These findings identify hematopoietic cells as a critical nexus for acute inflammatory driven anorexia as well as for chronic anorexia associated with malignant disease.
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| 10. |
- Toll John, Rani, 1975-, et al.
(författare)
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A cool response : the influence of ambient temperature on capillary refill time
- 2018
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Ingår i: Journal of Biophotonics. - : Wiley-VCH Verlagsgesellschaft. - 1864-063X .- 1864-0648. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveTo describe the effect of low ambient temperature on skin temperature and capillary refill (CR) time in forehead, sternum and finger pulp.MethodsAn observational, nonrandomized experimental study on 15 healthy subjects (6 females) in a cold room (8°C). Outcome measures were skin temperature and quantified CR test after application of a standardized blanching pressure (9 N/cm2) using digital photographic polarization spectroscopy to generate CR times.ResultsThe finger pulp showed marked temperature fall and prolonged CR times (>10 seconds). The CR registrations of the forehead and sternum were more comparable to curves observed in a control material at room temperature, and skin temperature falls were less marked. CR times were not prolonged in forehead measurements. At the sternum, some individuals showed CR times beyond guideline recommendations despite only a marginal reduction in skin temperature.ConclusionsLow ambient temperature is a strong independent factor for CR time at peripheral sites. Reservation about sternum as a site of measurement is warranted since cold provocation produced prolonged CR times in some individuals. We found that the forehead is the most thermostable of the 3 sites and thus the preferred site to avoid ambient temperature artifact in measuring CR time.
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