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Outcomes of Pediatric SARS-CoV-2 Omicron Infection vs Influenza and Respiratory Syncytial Virus Infections
No full textThis cohort study compares outcomes of SARS-CoV-2 Omicron infection with those of influenza or respiratory syncytial virus infection in pediatric patients attending the emergency department.</p
Oral Rehydration or Intravenous Drip? - A Volume Kinetic Study of Glucose Solutions to Young and Old
No full textBackground: The aim of this study was to use a volume kinetic model to compare oral versus intravenous fluid administration of glucose solutions in young and elderly healthy volunteers. We investigated differences in the absorption, distribution and elimination of the administered fluid. Methods: The study had a randomized, crossover design and all experiments were performed when subjects had been fasting overnight indicating a state of dehydration. Twenty-four healthy volunteers received an isotonic 2.5% glucose solution, 7 ml/kg during 15 minutes, both orally and intravenously at separate occasions. Repetitive blood tests over 120 minutes showed changes in body fluid volumes using volume kinetic principles. Results: There were significant different lag times of absorption between oral and intravenous administration of fluid. In the young, a plasma volume decrease was shown in the beginning of the oral rehydration experiments but they retained fluid at the end of the experiment. The elderly had a consistent slow elimination of glucose and retained water after oral rehydration. The two administration routes showed different patterns for the elderly’s fluid volume expansion with steeper slopes for intravenous rehydration. Conclusions: It was possible to model the absorption, distribution and elimination of glucose fluids given both orally and intravenously in both age groups.</p
Heterogeneity and aging of the hematopoietic stem cells
No full textStem cells are necessary for generating all cells in the body and are defined by two unique properties. First, their multilineage differentiation potential and second, their self-renewal ability.The hematopoietic stem cells (HSCs) are a rare population of cells that generate all blood cells in the human body and sit at the top of the hematopoietic hierarchy. However, the exact underlying molecular mechanisms that regulate their behavior remain partially obscure, which is a crucial part to elucidating HSC behavior. Previously, it was thought that the HSC population was homogeneous and generated all blood cells without any preference. However, this was disproved by various subsequent studies showing the presence of functionally different HSCs in the HSC pool. This included myeloid-biased (M-bi) HSCs, lymphoid-biased (L- bi) HSCs, and platelet-biased HSCs which show specific lineage differentiation preferences; as well as HSCs with a balanced output. Currently, the molecular mechanisms differentiating lineage-biased HSCs are unclear because they could not be prospectively isolated since the exact immunophenotypic definition of lineage-biased HSCs is not well characterized. As HSCs cannot be characterized based on cell surface markers, transplantation assays have to be done to confirm their long-term (LT) self-renewal and multilineage capability; highlighting the need to identify and understand the factors that discriminate them.Study I showed that CD49b is a reliable marker to further separate the conventional LT-HSC population into subpopulations that enrich for either the CD49b- M-bi or the CD49b+ L-bi HSCs. The two CD49b HSC populations differ in their chromatin accessibility even though gene expression comparisons showed no differences. This suggested that different HSCs are already primed to a preferred blood lineage before differentiation. The enrichment of lineage-biased HSCs in both CD49b populations demonstrated the usefulness of adding cell surface markers, though both CD49b subsets remain heterogeneous.Since residual heterogeneity in the HSC pool was observed in both CD49b subsets from study I, we attempted to further purify the functional LT-HSC population by including CD229 as a cell surface marker in study II. A multipotent progenitor (MPP) population was identified when both CD49b and CD229 were used in combination to subfractionate the LT-HSC pool. This showed that the addition of CD229 can help further purify the heterogeneous HSC population by eliminating the MPPs from the conventional LT-HSC population.Additional challenges in HSC studies, on top of a heterogeneous HSC population, is the reduction in hematopoietic system function with age, which leads to an overall decrease in HSC fitness and a higher chance of developing hematopoietic malignancies. One of the characteristics of an aging hematopoietic system is the increase in M-bi HSCs and a decrease in L-bi HSCs, but the underlying cause for such a shift in the HSC pool remains unclear.Therefore, to identify key regulators in directing HSC lineage bias and changes in HSCs with age, we studied the aging of CD49b HSC subpopulations in study III. From the in vivo studies, it was found that with age, both CD49b HSC subsets become more myeloid-biased. From the molecular studies, it was found that chromatin accessibility increases with age, that the additional accessibility gained in old age was de novo, and this gain of chromatin accessibility progresses through the adult age. Furthermore, it was suggested that the same transcriptional factor might be regulating both HSC aging and lineage bias.Taken together, studies I-III have shown that by adding cell surface markers in HSC selection, the HSC pool can be further purified and HSC subsets enriching for different lineage biases can be identified. Even though the subsets cannot be distinguished on the transcriptomic level, they show chromatin accessibility differences. In addition, we have found a potential transcription factor that is responsible for both HSC aging and lineage bias. These studies, taken together, not only help the field in understanding more about HSCs, but also provide the basis for future translational studies and therapeutic research.List of scientific papersI. Ece Somuncular, Julia Hauenstein, Prajakta Khalkar, Anne-Sofie Johansson, Özge Dumral, Nicolai S. Frengen, Charlotte Gustafsson, Giuseppe Mocci, Tsu-Yi Su, Hugo Brouwer, Christine L. Trautmann, Michael Vanlandewijck, Stuart H. Orkin, Robert Månsson, and Sidinh Luc. CD49b identifies functionally and epigenetically distinct subsets of lineage-biased hematopoietic stem cells. Stem Cell Reports. 2022 Jul 12;17(7). https://doi.org/10.1016/j.stemcr.2022.05.014II. Ece Somuncular*, Tsu-Yi Su*, Özge Dumral, Anne-Sofie Johansson, and Sidinh Luc. Combination of CD49b and CD229 reveals a subset of multipotent progenitors with short-term activity within the hematopoietic stem cell compartment. Stem Cells Transl Med. 2023 Nov 3;12(11). https://doi.org/10.1093/stcltm/szad057III. Tsu-Yi Su*, Julia Hauenstein*, Ece Somuncular*, Özge Dumral, Elory Leonard, Charlotte Gustafsson, Efthymios Tzortzis, Aurora Forlani, Anne-Sofie Johansson, Hong Qian, Robert Månsson, and Sidinh Luc. Aging is associated with functional and molecular changes in distinct hematopoietic stem cell subsets. Nat Commun. 2024 Sep 11;15(1):7966. https://doi.org/10.1038/s41467-024-52318-1*Equal contribution</p
Targeting neuronal NAD production through NMNAT2 for neuroprotection
No full textNicotinamide adenine dinucleotide (NAD) is a redox cofactor and a coenzyme essential for axonal health and neuronal survival. Increasing NAD levels has been suggested to be a promising approach to target neuroprotection in neurodegenerative diseases.In paper I, we demonstrate that NAD levels decrease in the retina and the optic nerve in a microbead occlusion model in rats with ocular hypertension (OHT). We also demonstrate that nicotinamide (NAM) can rapidly increase NAD levels in neuronal tissues (brain cortex, optic nerve, and retina) in a time-dependent manner.Alternative approaches to increase NAD levels are to target enzymes involved in the synthesis of NAD. Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a neuron-specific NAD synthase, which has been implied to be activated by the green tea polyphenol epigallocatechin gallate (EGCG).In paper II, we study the effects of EGCG on NAD levels and NMNAT2. We demonstrate that EGCG increases NAD levels in a dose- and time-dependent manner. However, due to EGCG's poor stability and bioavailability, we use it as a tool compound to generate more stable analogues to study the structure-activity relationship (SAR) between the compounds and their NAD-elevating effects. We generate 56 compounds and test their NAD-elevating effects and specificity towards neurons and the NAD salvage pathway. We identify multiple compounds that potently increase NAD levels and are neuroprotective in an ex vivo retinal explant model.Tetrahydroquinoxaline was the most potent core structure identified in paper II. Based on this, we generate tetrahydroquinoxaline derivatives to further study the SAR in paper III. We identify critical moieties for the NAD-boosting effect and assess whether the compounds are dependent on the salvage pathway to produce NAD.Our findings suggest that several of these novel compounds have significant potential as neuroprotective agents, providing valuable insights for further drug development.List of scientific papersI. Tribble JR, Otmani A, Sun S, Ellis SA, Cimaglia G, Vohra R, Jöe M, Lardner E, Venkataraman AP, Domínguez-Vicent A, Kokkali E, Rho S, Jóhannesson G, Burgess RW, Fuerst PG, Brautaset R, Kolko M, Morgan JE, Crowston JG, Votruba M, Williams PA. Nicotinamide provides neuroprotection in glaucoma by protecting against mitochondrial and metabolic dysfunction. Redox Biol. 2021;43:101988. https://doi.org/10.1016/j.redox.2021.101988II. Tribble JR*, Jöe M*, Varricchio C, Otmani A, Canovai A, Habchi B, Daskalakis E, Chaleckis R, Loreto A, Gilley J, Wheelock CE, Johannesson G, Wong RCB, Coleman MP, Brancale A, Williams PA. NMNAT2 is a druggable target to drive neuronal NAD production. Nature Communications. 2024;15(1):6256. *Co-first authors. https://doi.org/10.1038/s41467-024-50354-5III. Jöe M, Varricchio C, Cuřínová P, Nicol A, Saleh A, Wheelock CE, Johannesson G, Tribble JR, Brancale A, Williams PA. Novel tetrahydroquinoxaline derivatives increase NAD through the NAD salvage pathway. [Manuscript]</p
Autoantibodies and chronic pain : unraveling molecular mechanisms in rheumatoid arthritis
No full textAround one in five individuals worldwide experience chronic pain, making it a major public health concern. In rheumatoid arthritis (RA), pain is a defining characteristic and a leading reason for patients to consult a physician. However, pain management in RA remains challenging, as it can appear before diagnosis and persist even after treatment with disease-modifying antirheumatic drugs (DMARDs). This indicates that inflammation and pain are not always closely linked. The presence of autoantibodies in RA, which are often used as diagnostic markers, has prompted the establishment of mouse models that replicate the disease at different stages and help uncover its underlying mechanisms. Therefore, this thesis aims to investigate potential mechanisms of autoantibodies that may clarify the relationship between pain and RA during both the pre-inflammatory and low-grade inflammatory stages of the disease.In Study 1, we examined the link between bone degradation, pain, and inflammation by utilizing two monoclonal antibodies (mAbs) obtained from B- lymphocytes of RA patients. This study focused on the role of osteoclast activity, which is often heightened in various bone disorders and contributes to both bone remodeling and pain sensitivity. By combining the patient-derived antibodies B02 and B09, we observed that mice injected with these antibodies developed persistent mechanical hypersensitivity and reduced bone mass without overt signs of inflammation in the affected joints. Notably, we observed upregulation of pro-inflammatory genes in the ankle joints of B02/B09 injected mice, but application of classical non-steroidal anti-inflammatory drugs (NSAIDs) lacked an effect on pain-like behavior. Furthermore, blocking osteoclast-mediated processes and acid-sensing ion channel 3 (ASIC3) signaling effectively mitigated the hypersensitivity induced by the antibodies. Additionally, we determined secretory phospholipase A2 (sPLA2) and lysophosphatidylcholine 16:0 (LPC 16:0) as key contributors to B02/B09 evoked pain-related behavior. This study reveals a previously unexplored association between bone degradation and pain during subclinical inflammation in an animal model of preclinical RA and offers new insights into osteogenic pain mechanisms.For Study 2, we focused on the effects of B09 mAb alone, aiming to deepen our understanding of how a single antibody can induce pain-like behavior. Injection of this anti-modified protein antibody causes hypersensitivity in mice, that in contrast to the B02/B09 combination is not coupled to bone loss or subclinical inflammation within ankle joints. Further investigation revealed B09 accumulation in the dorsal root ganglia (DRGs) and the increased production of various factors related to satellite glial cells (SGCs), neurons, and macrophages. Through experiments with mice lacking activating Fcy receptors (FcyRs), we demonstrated that these receptors are essential for B09 to initiate pain-related behavior and play a role in the resulting mRNA changes in the DRGs. Furthermore, we found that B09 mAb binds to cultured SGCs and, when combined with additional stimuli, such as adenosine triphosphate (ATP), causes expression and secretion of pain- inducing mediators. This study reinforces the concept that autoantibodies can influence nociception via mechanisms independent of local joint inflammation.In Study 3, we utilized the RA patient-derived anti-citrullinated protein antibody C03, which was recently reported to possess anti-inflammatory properties. From this perspective we were intrigued to investigate whether C03 exerts pro- nociceptive properties that could be interpreted as a warning signal instead of a driver for disease development. While some of our in vitro experiments indicated that C03 decreases level of pro-inflammatory and pro-nociceptive molecules, our in vivo data showed opposing indications. When injected into mice, C03 causes slight pro-inflammatory and pro-nociceptive alterations in gene expression in ankle joints and induces pain-related behaviors. This included Chemokine (C-X-C motif) ligand 1 (Cxcl1), osteoclast and nerve growth related factors and is supported by anti-nociceptive effects of CXCR1/2 antagonism and partial analgesic effects of osteoclast inhibition and nerve growth factor (NGF) neutralization. To follow up on our findings from Study 2 we investigated the presence of C03 in the DRGs and found increased expression of pain-related mediators, while interestingly no local accumulation could be detected. We rather suggest a peripheral stimulation of nociceptors as C03 could be found bound to monocyte-derived cells in the synovium of the ankle joint following intra-articular injection. In short, we hypothesize that C03 causes pain-related behaviors by acting on immune cells in the joints, but additional experiments are crucial to clarify the disconnect between the results of our cell culture and animal experiments.In the context of Study 4, our goal was to investigate the effects of Janus kinase (JAK) inhibitor baricitinib on RA pain that persists beyond the resolution of inflammation. This study was motivated by clinical reports indicating that the positive effects of this JAK1/2 inhibitor on pain relief cannot be entirely attributed to its anti-inflammatory properties, and that its effectiveness appears to surpass that of Tumor necrosis factor (TNF) inhibitors. We employed the collagen antibody-induced arthritis (CAIA) model, where mice develop lasting mechanical hypersensitivity that outlasts after visible joint inflammation has subsided. We found that baricitinib treatment dose-dependently inhibited the development of inflammation during early, inflammatory CAIA, but only ameliorated mechanical hypersensitivity during the low-grade inflammatory (=late) phase of CAIA. Interestingly, no effect of the TNF inhibitor etanercept on pain-like behavior during post-inflammatory CAIA was observed. With additional experiments we discovered that baricitinib exerts differential effects that either are inflammation- dependent or independent. When we applied baricitinib during the inflammatory together with the late phase of the model, we observed an osteoprotective effect on the calcaneus bone of the ankle and a reduction of phosphorylated signal transducer and activator of transcription 3 (STAT3) protein in ankle joints and DRGs. Furthermore, this treatment regimen was able to normalize innervation of the synovial membrane, which was increased in late phase CAIA mice. Strikingly, treating mice exclusively during the late phase of the model did not ameliorate CAIA-induced bone degradation, but also had a potent anti-nociceptive effect with rapid onset. With complementary in vitro experiments we found that baricitinib can decrease neuronal excitability and alters glia cell morphology. During the screening process for antiviral drugs amid the coronavirus disease (COVID)-19 pandemic, it was discovered that baricitinib also inhibits AP2- Associated Kinase 1 (AAK1) signaling, a key part of clathrin-mediated endocytosis (CME). Interestingly, this process is not only involved in receptor internalization and intracellular trafficking, but also reported to play a role in neuropathic pain. In our study, baricitinib suppressed AAK1 signaling in DRGs, and specifically inhibiting AAK1 during late phase CAIA restored mechanical hypersensitivity. In conclusion, this study revealed molecular mechanisms behind baricitinib mediated pain relief and emphasized that JAK and AAK1 pathways might be promising therapeutic targets for alleviating pain for RA patients.To summarize, this thesis investigates the complex interplay between autoantibodies and pain in RA, revealing novel mechanisms that could underlie persistent pain beyond inflammation. These findings provide important perspectives on potential therapeutic targets, paving the way for developing more efficacious pain-relieving therapeutics for RA patients.List of scientific papersI. Antibody-induced pain-like behavior and bone erosion: links to subclinical inflammation, osteoclast activity, and acid-sensing ion channel 3-dependent sensitization. Alexandra Jurczak*, Lauriane Delay*, Julie Barbier, NILS SIMON, Emerson Krock, Katalin Sandor, Nilesh M. Agalave, Resti Rudjito, Gustaf Wigerblad, Katarzyna Rogoz, Arnaud Briat, Elisabeth Miot- Noirault, Arisaí Martínez-Martínez, Dieter Brömme, Caroline Grönwall, Vivianne Malmström, Lars Klareskog, Spiro Khoury, Thierry Ferreirag, Bonnie Labrum, Emmanuel Deval, Juan Miguel Jiménez-Andrade, Fabien Marchand#, Camilla I. Svensson#. Pain. 2022 August, p 1542- 1559. https://doi.org/10.1097/j.pain.0000000000002543Il. Insights into FcyR involvement in pain-like behavior induced by an RA-derived anti-modified protein autoantibody. Alexandra Jurczak, Katalin Sandor, Alex Bersellini Farinotti, Emerson Krock, Matthew A. Hunt, Nilesh M. Agalave, Julie Barbier, NILS SIMON, Zhenggang Wang, Resti Rudjito, Juan Antonio Vazquez-Mora, Arisaí Martínez-Martínez, Ramin Raoof, Niels Eijkelkamp, Caroline Grönwall, Lars Klareskog, Juan Miguel Jiménez-Andrade, Fabien Marchand, Camilla I. Svensson. Brain, Behavior, and Immunity. 2023 October, p 212-227. https://doi.org/10.1016/j.bbi.2023.07.001III. Monoclonal anti-citrullinated protein antibody 1325:04C03 causes pain-like behavior in mice by osteoclast stimulation, CXCR1/2, and NGF signaling. NILS SIMON*, Alexandra Kuliszkiewicz*, Katalin Sandor*, Julie Barbier, Alex Bersellini Farinotti, Arisaí Martínez-Martínez, Juan Antonio Vazquez Mora, Enriqueta Muñoz Islas, Carlos E. Morado Urbina, Matthew Hunt, Kirill Agashkov, Heidi Wähämaa, Vivianne Malmström, Lars Klareskog, Bence Rethi, Caroline Grönwall, Fabien Marchand, Juan Miguel Jiménez-Andrade, Camilla I. Svensson. [Manuscript]IV. Characterization of the anti-nociceptive effect of baricitinib in the collagen antibody-induced arthritis mouse model NILS SIMON*, Resti Rudjito*, Lydia Moll, Katalin Sandor, Juan Antonio Vazquez Mora, Zerina Kurtović, Alexandra Kuliszkiewicz, Carlos E. Morado Urbina, Sven David Arvidsson, Eduardo Mendoza-Sánchez, Giovanni E. López-Delgado, Qing Luo, Qiaolin Deng, Arisaí Martínez- Martínez, Jens Gammeltoft Gerwien, Paul Karila, Venkatesh Krishnan, Juan Miguel Jiménez-Andrade, Camilla I. Svensson. [Submitted]*,# contributed equally</p
Damage-associated molecular patterns and pathogen-associated molecular patterns in severe bacterial infections
No full textCommunity-acquired bacterial infections can range from mild to severe, including sepsis. The mechanisms driving severe disease and poor outcomes remain unclear. The early host response in sepsis is triggered by pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), which activate the innate immune system. However, the relationship between DAMP and PAMP levels, their dynamics during the disease, and their role in the development of severe illness, is not fully understood. This thesis aimed to explore DAMPs and PAMPs in severe bacterial infections, focusing on their interrelationship and how their systemic and local concentrations correlate with disease severity.Study I assessed the relationship between clinical and microbiological factors and the nasopharyngeal (NP) density of Streptococcus pneumoniae in 57 adults hospitalised with pneumococcal community-acquired pneumonia (CAP) and whether high NP density could indicate severe disease. It was found that high NP pneumococcal density was linked to severe pneumonia, longer symptom duration (≥2 days), and a higher serum immunoglobulin titre against the patient’s pneumococcal serotype. However, NP density was not found to be useful for reliably detecting severe pneumococcal pneumonia.In Study II, we investigated the relationship between high mobility group box 1 (HMGB1), a DAMP, and lytA DNA load, a PAMP, with disease severity and aetiology in CAP. Among 111 hospitalised patients, HMGB1 levels in plasma and sputum showed no correlation with disease severity. However, elevated sputum HMGB1 was associated with pneumococcal aetiology. In cases of pneumococcal CAP, a high sputum lytA DNA load was linked to respiratory failure, while elevated sputum HMGB1 was associated with bacteraemia. These findings indicate that although sputum HMGB1 is not associated with disease severity, it may play a role in bacterial dissemination, whereas a high lytA load is associated with severe disease.Study III analysed whether plasma and sputum levels of soluble thrombomodulin were associated with disease severity in 111 patients with bacterial CAP and whether these levels varied across different bacterial aetiologies. Plasma thrombomodulin concentrations were elevated in patients with severe pneumococcal CAP, but not in those with severe CAP caused by other bacteria or in cases of non-severe pneumococcal CAP. This suggests that plasma thrombomodulin may serve as a potential biomarker for detecting severe pneumococcal pneumonia. Conversely, sputum thrombomodulin concentrations were not associated with disease severity or bacterial aetiology. Study IV examined the role of four DAMPs, nuclear DNA (nDNA), mitochondrial DNA (mtDNA), heat shock protein 90 alpha (HSP90α), and HMGB1, and their dynamics in relation to disease severity and negative outcomes, compared to the previously analysed PAMP, 16S rDNA, in a cohort of 83 patients with bacteraemic infections caused by S. pneumoniae, Staphylococcus aureus, or Escherichia coli. Among the DAMPs, nDNA outperformed the others in sepsis detection and outcome prediction. In the comparison between DAMP and PAMP, a significant correlation was observed between them; nevertheless, both nDNA (a DAMP) and 16S rDNA (a PAMP) were independently associated with sepsis, with nDNA also being linked to negative outcomes and remaining persistently elevated in these cases.List of scientific papersI. Clinical and microbiological factors associated with high nasopharyngeal pneumococcal density in patients with pneumococcal pneumonia. Helena Alpkvist, Simon Athlin, Pontus Nauclér, Björn Herrmann, Guma Abdeldaim, Hans-Christian Slotved, Jonas Hedlund, Kristoffer Strålin. PLoS One, 2015 Oct 14;10(10):e0140112. https://doi.org/10.1371/journal.pone.0140112II. High HMGB1 levels in sputum are related to pneumococcal bacteraemia but not to disease severity in community-acquired pneumonia. Helena Alpkvist, Simon Athlin, Paula Mölling, Anna Norrby-Teglund, Kristoffer Strålin. Scientific Reports, 2018 Sep 7;8(1):13428. https://doi.org/10.1038/s41598-018-31504-4III. Plasma and sputum thrombomodulin in bacterial community-acquired pneumonia. Helena Alpkvist, Simon Athlin, Anna Norrby-Teglund, Kristoffer Strålin. [Submitted]IV. Damage-associated molecular patterns in bacteraemic infection, including a comparative analysis with bacterial DNA, a pathogen-associated molecular pattern. Helena Alpkvist, Ingrid Ziegler, Paula Mölling, Elisabet Tina, Linnea Sellvén, Anna Norrby-Teglund, Sara Cajander, Kristoffer Strålin. Scientific Reports, 2024 Oct 8;14(1):23499. https://doi.org/10.1038/s41598-024-74868-6 * = equal contribution.</p
Lifestyle and medical conditions in relation to ALS risk and progression-an introduction to the Swedish ALSrisc Study.
No full textBACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis
Epidemiological studies of electroconvulsive therapy for depression
No full textMajor depressive disorder is a condition that causes great suffering and substantial disability world-wide. Severe forms of major depressive disorder (MDD) are also associated with a high risk of suicide. For severe forms of MDD, ECT is the most effective treatment. ECT is generally well tolerable but there are side-effects. Memory disturbances are the most common complaint. During the procedure the patient is sedated but there is no consensus on optimal anaesthetic regime. Even though ECT often relieves the symptoms greatly, MDD is often a recurring condition and relapse the first six months is common. As of now there is no consensus on optimal pharmacological treatment strategy post ECT.In study I we investigated the effect of electrical charge on subjective memory worsening. The study was a register-based cohort-study. Data was gathered from the Q-ECT. The study included 154 patients. 57 patients had received a higher electrical charge, and 97 patients received a lower electrical charge. Subjective memory worsening (SMW) was measured with a global memory rating scale (CPRS-M). There was a significant difference in SMW among the two groups, patients with a higher electrical charge had a higher occurrence of SMW compared to patients with a lower electrical charge (44% vs 25%, p=0.014). There was no significant difference in terms of relief of depressive symptoms between the two groups. The study concluded that there are limited benefits of a high electrical charge compared to a moderate.In study II we wanted to explore prescription patterns and compare the effect of different pharmacological strategies on risk of relapse following ECT for MDD among patients who responded distinctively to the initial treatment. The study included a total of 2858 patients, and the risk of relapse was investigated during the first year after ECT. Relapse in MDD was defined as; suicide, attempted suicide, psychiatric rehospitalisation or renewed ECT. During the first year of follow-up 52.2% of patients relapsed, according to our definition. We used a Cox proportional hazards model to calculated adjusted hazard ratios (HR). The model was adjusted for several factors including age, sex, psychiatric comorbidity and previous pharmacological treatment attempts. We found a non-significant association between dispensation of lithium and a lower risk of relapse (HR 0.86, 95% CI 0.69-1.07, p=0.17). Dispensation of antipsychotics were associated with an increased risk of relapse (HR 1.17, 95% CI 1.05-1.31, p=0.006).In study III we examined the effect of anaesthetic dosage intervals on the antidepressant effect of ECT. The study was a register-based cohort study and included 7197 patients. We compared high, medium, and low dosage intervals associations with response to treatment. The primary outcome was measured with the Clinical Global Impressions - Improvement Scale (CGI-I). Secondary outcomes were remission from depressive symptoms, measured with the Montgomery-Åsberg Depression Self-rating scale (MADRS-S). We used a logistic regression model and calculated adjusted odds ratios. The model was adjusted for several factors including age, sex, psychiatric comorbidity and number of treatments. We found that a lower dosage, compared to high, was associated with a greater chance of response (OR 1.22, 95% CI 1.07-1.40, P = 0.004). There was an increase of reported SMW among the patients who received a lower dosage interval, most likely attributed to the increased seizure duration and activity. In conclusion, lower dosage intervals of anaesthetics improve treatment outcome but could potentially increase reports of SMW.In study IV we investigated patient attitudes towards renewed ECT treatment after receiving ECT for MDD. Patients who received ECT for MDD participated in a six-month follow-up. During this follow-up, patients were asked if they would accept renewed ECT under similar circumstances. A total of 1917 patients were included in the study. Among these, 51.1% of patients were positive, 27.6% undecided and 21.3% negative towards receiving ECT under similar circumstances at the time of the six-month follow up. We examined which factors were associated a negative attitude towards renewed ECT. Adjusted odds ratios were calculated using a logistic regression model. Patients who responded to treatment were less likely to have a negative attitude towards renewed ECT (odds ratio 0.32, 95% CI 0.25-0.41, P List of scientific papersI. Kronsell A, Nordenskjöld A, Tiger M. Less memory complaints with reduced stimulus dose during electroconvulsive therapy for depression. J Affect Disord. 20 augusti 2019;259:296-301. https://doi.org/10.1016/j.jad.2019.08.064Il. Kronsell A, Nordenskjold A, Boden R, Mittendorfer-Rutz E, Reutfors J, Rossides M, Tiger M. Real-world analysis of pharmacological treatments to prevent relapse after electroconvulsive therapy for major depressive disorder: A nation-wide cohort study. [Manuscript]III. Kronsell A, Nordenskjold A, Bell M, Amin R, Mittendorfer-Rutz E, Tiger M. The effect of anaesthetic dose on response and remission in electroconvulsive therapy for major depressive disorder: nationwide register-based cohort study. BJPsych Open. 23 mars 2021;7(2):e71. https://doi.org/10.1192/bjo.2021.31IV. Kronsell A, Nordenskjöld A, Mittendorfer-Rutz E, Tiger M. Long-term follow-up on patient attitudes towards renewed ECT: A register-based cohort study. J Psychiatr Res. 25 juni 2024;177:24-30. https://doi.org/10.1016/j.jpsychires.2024.06.040</p
A tale of two fronts : novel experimental strategies to improve stroke outcome in type 2 diabetes
No full textBackgroundType 2 Diabetes (T2D) constitutes a critical health issue worldwide, which is associated with poor stroke outcome and lasting disability. However, the exact mechanisms through which T2D worsens stroke outcome are not determined and despite the high medical need for therapies, no treatment is currently available. The hypothesis behind this thesis was built on the concept that by targeting the impaired T2D metabolism either before or after stroke, stroke outcome could be improved.AimThe aim of this thesis was to therefore investigate whether a weight loss (WL) intervention (mimicking a lifestyle intervention) before stroke (Paper I: diet change) as well as several pharmacological interventions with antidiabetic treatments implemented either before (Paper II: Glucagon-like peptide-1 receptor (GLP-1R)/Neuropeptide Y receptor Y2 (NPY2R) co-activation) or after stroke (Papers III, IV: GLP-1R activation & Sodium-glucose cotransporter-2 (SGLT2) inhibition) improve stroke outcome in T2D mice and to identify some of the underlying mechanisms.MethodsTo achieve these aims, C57BL/6J mice were fed with high-fat diet (HFD) for several months to induce obesity and T2D features (i.e. hyperglycemia and insulin resistance). Thereafter, the mice received either a diet change leading to WL or pharmacological interventions before (Papers I, II) or after (Papers III, IV) a stroke induced by transient middle cerebral artery occlusion (tMCAO). The chronic stroke outcome was assessed by measuring the recovery of the grip strength and/or the lateralized sensorimotor integration of the mice several weeks after tMCAO, until sacrifice. Mouse brains were then collected and various immunohistochemical assessments were performed.ResultsAll the aforementioned interventions (Papers I-IV) in the T2D mice resulted in better stroke outcome compared to the diabetic controls, suggesting that the improved metabolism in T2D before or after stroke, was beneficial to improve stroke outcome. Several mechanisms by which stroke outcome was ameliorated in the treatment groups were also identified.In Paper I, the 4-month dietary change leading to WL before tMCAO, which improved fasting glycemia and insulin sensitivity, resulted in improved stroke outcome in association with decreased cellular atrophy of GABAergic parvalbumin (PV)+ interneurons and neuroinflammation, as well as reduced astrocyte reactivity in contralateral striatum.In Paper II, GLP-1R activation by Semaglutide induced a significant WL before tMCAO, upstream of glycemia regulation, which resulted in improved post-stroke outcome. These effects were further enhanced by NPY2R co-activation by the NPY2R agonist BI8271 in association with the normalization of peripheral insulin- like growth factor 1 (IGF-1) and homocysteine levels. Furthermore, GLP-1R and NPY2R activation exerted acute neuroprotection, which was independent of their metabolic effects.In Paper III, the GLP-1R activation by Exendin-4 after tMCAO improved glucose metabolism and resulted in improved stroke outcome in association with the counteraction of T2D-induced atrophy of PV+ interneurons and the reduction of T2D-induced microglial neuroinflammatory response.In Paper IV, the SGLT2 inhibition by Empagliflozin after tMCAO resulted in improved stroke outcome in the diabetic mice via the normalization of glycemia, but not insulin sensitivity, in association with increased serum fibroblast growth factor 21 (FGF-21) and normalized parenchymal pericyte density.ConclusionIn an era of obesity and diabetes, with a high prevalence of cardiovascular complications, including stroke, specific strategies to ameliorate the poor stroke outcome in T2D are highly needed. To this end, four strategies are proposed in this thesis that could be evaluated in future clinical trials; two offering a prophylactic (Papers I, II; before stroke) and two a curative (Papers III, IV; after stroke) value. A pre-stroke dietary intervention and the repurposing of several clinically used antidiabetic treatments, either pre- or post-stroke, are hereby suggested to offer novel therapeutic options to improve stroke outcome for numerous people.List of scientific papersI. Karampatsi, D. et al. Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke. Cardiovasc Diabetol 20, 240. https://doi.org/10.1186/s12933-021-01426-zII. Karampatsi, D. et al. Pre-Stroke Weight Loss by Glucagon-like Peptide 1 Receptor and Neuropeptide Y Receptor Y2 Activation improves Post-Stroke Functional Recovery in T2D mice. [Submitted]III. Augestad, I. L. & Dekens, D., Karampatsi, D. et al. Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice. Br J Pharmacol. https://doi.org/10.1111/bph.15524IV. Vercalsteren, E., Karampatsi D., et al. The SGLT2 inhibitor Empagliflozin promotes post-stroke functional recovery in diabetic mice. Cardiovasc Diabetol 23, 88, (2024). https://doi.org/10.1186/s12933</p
Cognitive behavioural therapy for insomnia : a comparison between sleep compression and sleep restriction
No full textBackground: Insomnia is a common and debilitating disorder with significant personal and societal costs. Cognitive behavioural therapy for insomnia (CBT-I) is an effective treatment, with sleep restriction therapy being a key component. However, sleep restriction therapy can be difficult for some patients to tolerate due to the initial sleep deprivation often associated with the treatment. Sleep compression therapy has been proposed as a gentler alternative. This thesis investigates the efficacy, tolerability, and impact of sleep compression therapy in comparison to sleep restriction therapy, as well as the correlation between change in subjective and objective sleep measures. Additionally, it explores the variations in time-in-bed manipulation therapies across the literature.Methods: The thesis includes three studies and preliminary results from a fourth study. Studies 1-3 were based on the CompRest trial (NCT02743338), a randomised controlled trial of 234 participants with chronic insomnia, recruited via the Internet Psychiatry Clinic in Stockholm, Sweden. Participants were randomised to either sleep compression therapy (COMP) or sleep restriction therapy (REST), both delivered online with therapist support for five weeks followed by five weeks of self-administered treatment. Sleep was measured subjectively using the Insomnia Severity Index (ISI), and sleep diaries, while objective data were collected via actigraphy, and also polysomnography (PSG) for a subgroup (n=36). Study 1 focused on insomnia severity and tolerability of treatment, Study 2 on objective sleep, and Study 3 explored the correlation between subjective and objective sleep changes. Study 4 was a scoping review of time-in-bed manipulation therapies in the literature, registered with the Open Science Framework.Results: In Study 1, both COMP and REST significantly reduced insomnia severity after ten weeks. However, COMP was not found to be non-inferior to REST, as the confidence interval of the ISI difference crossed the non-inferiority threshold of 1.6 points. In terms of tolerability, COMP had fewer reported side effects in the early weeks and demonstrated better adherence in two out of three measures, though there were no differences in client satisfaction or daytime functioning between the treatments.In Study 2, objective sleep measures (PSG) showed that both treatments resulted in similar sleep outcomes after 10 weeks, though REST was associated with a larger and more rapid decrease of total sleep time and time in bed. No significant differences were observed for sleep continuity variables or sleep stages between the treatments.Study 3 investigated correlations between subjective and objective sleep changes. Significant correlations were found between improvements in subjective sleep quality (Karolinska Sleep Quality Index) and reductions in time in bed, sleep onset latency, and increases in sleep efficiency, as measured by PSG. Additionally, improvements in the Restorative Sleep Index were correlated with sleep efficiency increases, fewer awakenings, and a reduction in N3 sleep. However, no significant correlations were found between changes in the ISI and objective sleep measures.In Study 4 (preliminary results), a scoping review of time-in-bed manipulation therapies, 52 studies, covering 60 interventions, were included. There was considerable variation in the methods for calculating the initial sleep window, with nine different approaches identified. No clear consistency emerged between the naming of the intervention and the calculation of the sleep window. Other instructions, such as nap allowances and the safe lower limits for time in bed, also varied widely. Half of the included studies were randomised controlled trials, and eight directly compared different brief time-in-bed manipulation interventions.Conclusions: This thesis provides new insights into the efficacy and tolerability of sleep compression therapy as an alternative to sleep restriction therapy for treating insomnia. While sleep compression therapy was not non-inferior to sleep restriction therapy in reducing insomnia severity, it was better tolerated, suggesting it may be a suitable alternative for patients who struggle with the initial sleep deprivation associated with sleep restriction therapy. Both treatments had similar impacts on subjective and objective sleep after ten weeks, though with different trajectories of change. Additionally, subjective improvements in sleep quality were linked to objective changes in sleep parameters, highlighting the potential of addressing change when investigating objective correlates of subjective experiences of sleep. The scoping review revealed substantial variation in time-in- bed manipulation therapies, underscoring the need for further research to compare different approaches.List of scientific papersThe following manuscripts and publications were included in the thesis:I. Jernelöv, S .* , Rosén, A .* , Forsell, E., Blom, K., Ivanova, E., Maurex, L., Jansson-Fröjmark, M., Åkerstedt, T., Kaldo, V. Is sleep compression therapy non-inferior to sleep restriction therapy? A single blind randomized controlled non-inferiority trial comparing sleep compression therapy to sleep restriction therapy as treatment for insomnia. [Manuscript]II. Rosén, A., D'Onofrio, P., Åkerstedt, T. & Jernelöv, S. (2023). A comparison of sleep restriction and sleep compression on objective measures of sleep: a sub-sample from a large randomized controlled trial, Journal of sleep research, 32(4), e13826. https://doi.org/10.1111/jsr.13826III. d'Onofrio, P., Jernelöv, S., Rosén, A., Blom, K., Kaldo, V., Schwarz, J., & Åkerstedt, T. (2023). The Polysomnographical Meaning of Changed Sleep Quality-A Study of Treatment with Reduced Time in Bed. Brain Sciences, 13(10), 1426. https://doi.org/10.3390/brainsci13101426*Authors contributed equally</p