| 1. |
- Agrasada, Grace V., et al.
(författare)
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Exclusive breastfeeding of low birth weight infants for the first six months : infant morbidity and maternal and infant anthropometry
- 2011
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Ingår i: Asia Pacific Journal of Clinical Nutrition. - : H E C Press. - 0964-7058 .- 1440-6047. ; 20:1, s. 62-68
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Tidskriftsartikel (refereegranskat)abstract
- Background: to report anthropometry and morbidity among term low birth weight infants and anthropometry of their first time mothers during the first six months in relation to breastfeeding practice. Methods: we examined data from a randomized controlled trial in Manila, the Philippines. Of the 204 mothers randomized, 68 mothers received eight postpartum breastfeeding counseling sessions, the rest did not. Maternal and infant anthropometric data at birth, 2, 4 and 6 months were taken. During seven follow-up hospital visits, an independent interviewer recorded feeding data. Results: the 24 infants exclusively breastfed from birth to six months did not have diarrhea compared to 134 partially breastfed (mean 2.3 days) and 21 non-breastfed infants (mean 2.5 days). Partially breastfed and non-breastfed infants compared to exclusively breastfed infants had more frequent, as well as more severe episodes of respiratory infections. At six months, neither overall gain in infant weight, length and head circumferences nor mean maternal weight and body mass index differed significantly between the feeding groups. Conclusions: exclusive breastfeeding for 6 months can be recommended in term low birth weight infants, who were protected from diarrhea, had fewer respiratory infections, required no hospitalization and had catch up growth. Exclusively breastfeeding mothers did not differ from mothers who breastfed partially or those who did not breastfeed with regard to weight changes at six months.
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| 2. |
- Badam, Tejaswi, et al.
(författare)
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CD4(+) T-cell DNA methylation changes during pregnancy significantly correlate with disease-associated methylation changes in autoimmune diseases
- 2022
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Ingår i: Epigenetics. - : Taylor & Francis Group. - 1559-2294 .- 1559-2308. ; 17:9, s. 1040-1055
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetics may play a central, yet unexplored, role in the profound changes that the maternal immune system undergoes during pregnancy and could be involved in the pregnancy-induced modulation of several autoimmune diseases. We investigated changes in the methylome in isolated circulating CD4(+) T-cells in non-pregnant and pregnant women, during the 1(st) and 2(nd) trimester, using the Illumina Infinium Human Methylation 450K array, and explored how these changes were related to autoimmune diseases that are known to be affected during pregnancy. Pregnancy was associated with several hundreds of methylation differences, particularly during the 2(nd) trimester. A network-based modular approach identified several genes, e.g., CD28, FYN, VAV1 and pathways related to T-cell signalling and activation, highlighting T-cell regulation as a central component of the observed methylation alterations. The identified pregnancy module was significantly enriched for disease-associated methylation changes related to multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus. A negative correlation between pregnancy-associated methylation changes and disease-associated changes was found for multiple sclerosis and rheumatoid arthritis, diseases that are known to improve during pregnancy whereas a positive correlation was found for systemic lupus erythematosus, a disease that instead worsens during pregnancy. Thus, the directionality of the observed changes is in line with the previously observed effect of pregnancy on disease activity. Our systems medicine approach supports the importance of the methylome in immune regulation of T-cells during pregnancy. Our findings highlight the relevance of using pregnancy as a model for understanding and identifying disease-related mechanisms involved in the modulation of autoimmune diseases.
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| 3. |
- Gustafsson, Erik, et al.
(författare)
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Mathematical modelling of the regulation of spa (protein A) transcription in Staphylococcus aureus.
- 2009
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Ingår i: International journal of medical microbiology : IJMM. - : Elsevier BV. - 1618-0607 .- 1438-4221. ; 299:1, s. 65-74
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Tidskriftsartikel (refereegranskat)abstract
- In the present work a general systems biology approach has been used to study the complex regulatory network controlling the transcription of the spa gene, encoding protein A, a major surface protein and an important virulence factor of Staphylococcus aureus. A valid mathematical model could be formulated using parameter values, which were fitted to quantitative Northern blot data from various S. aureus regulatory mutants using a gradient search method. The model could correctly predict spa expression levels in 4 different regulatory mutants not included in the parameter value search, and in 2 other S. aureus strains, SH1000 and UAMS-1. The mathematical model revealed that sarA and sarS seem to balance each other in a way that when the activating impact of sarS is small, e.g. in the wild-type, the repressive impact of sarA is small, while in an agr-deficient background, when the impact of sarS is maximal, the repressive impact of sarA is close to its maximum. Furthermore, the model revealed that Rot and SarS act synergistically to stimulate spa expression, something that was not obvious from experimental data. We believe that this mathematical model can be used to evaluate the significance of other putative interactions in the regulatory network governing spa transcription.
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| 4. |
- Gustafsson, Erik, et al.
(författare)
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Maximal transcription of aur (aureolysin) and sspA (serine protease) in Staphylococcus aureus requires staphylococcal accessory regulator R (sarR) activity
- 2008
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Ingår i: FEMS Microbiology Letters. - : Blackwell Publishing. - 0378-1097 .- 1574-6968. ; 284:2, s. 158-164
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have shown that expression of aur (metalloprotease; aureolysin) and sspA (V8 protease; serine protease) in Staphylococcus aureus strain 8325-4 is maximal in the postexponential phase of growth, when the agr (RNAIII) system is activated. Transcription of aur and sspA is mainly regulated through repression by sarA and rot, and RNAIII stimulates protease production by inhibiting translation of rot mRNA. As SarR is a repressor of sarA, inactivation of sarR would result in downregulation of aur and sspA transcription. This was confirmed by mRNA analysis using quantitative real-time PCR. However, we found that sarR acted as a direct stimulator, i.e. its positive effect on aur and sspA transcription did not require sarA (or rot) per se. In addition, aur and sspA were dependent on sarR for maximal transcription. This stimulating role of sarR was not restricted to the rsbU-deficient laboratory strain 8325-4 but was also demonstrated in S. aureus strain SH1000 (rsbU-complemented derivative of 8325-4) and in one clinical isolate.
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| 5. |
- Johansson, Anna, et al.
(författare)
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Evaluation of an individualised programme to promote self-care in sleep-activity in patients with coronary artery disease - a randomised intervention study
- 2014
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Ingår i: Journal of Clinical Nursing. - : Wiley-Blackwell Publishing Inc.. - 0962-1067 .- 1365-2702. ; 23:19-20, s. 2822-2834
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Tidskriftsartikel (refereegranskat)abstract
- Aims and objectives: To evaluate the effectiveness of an individualised programme to promote self-care in sleep-activity in patients with coronary artery disease. Background: Recent scientific findings have shown that low physical exercise and stress interfere with coronary artery disease patients' sleep quality and sleep efficiency independent of gender, age and co-morbidity. Design: A randomised pretest-post-test control design. Methods: Forty-seven patients who had undergone a coronary revascularisation procedure and/or pharmacological treatment three to seven weeks earlier at a general hospital were randomised to either an intervention group or a control group. Data collection was carried out by questionnaires, a study-specific sleep diary and actigraphy registration for 10 consecutive 24-hour periods, with a follow-up after three to four months. The intervention group underwent a nurse-led individualised education programme to promote self-care of sleep-activity. Sleep habits and sleep-related lifestyle together formed the basis for setting up individual goals together with the nurse. Individual advice on physical training, relaxation exercise and a CD-based relaxation programme was provided by a physiotherapist. Both groups received a brochure about sleep and stress. Results: At a three- to four-month follow-up, the main improvements were seen in the intervention group regarding sleep quality, sleep duration and sleep efficiency in the sleep diary and sleep efficiency in actigraphy. Statistical improvements in health-related quality of life were revealed. This was not so obvious in the control group. Conclusions: An individualised intervention programme to promote self-care of sleep-activity including relaxation in patients with coronary artery disease led by a nurse may improve sleep quality. However, a longitudinal study to promote self-care in sleep-activity should be performed using a larger sample and multiple sites with continuous follow-ups to determine whether any positive effects remain stable over time. Relevance to clinical practice: Implementation of a multiprofessional individualised programme to promote self-care of sleep-activity including relaxation based on patients' needs, supported by a healthcare team and led by nurses, is important in clinical practice. © 2014 John Wiley & Sons Ltd.
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| 6. |
- Johansson, Anna, et al.
(författare)
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Sleep, arousal and health-related quality of life in men and women with coronary artery disease.
- 2011
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Ingår i: Journal of Clinical Nursing. - : Blackwell. - 0962-1067 .- 1365-2702. ; 20:19-20, s. 2787-2801
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Tidskriftsartikel (refereegranskat)abstract
- Aim. To evaluate whether there are gender differences in insomnia, sleep quality, sleep efficiency (%), general arousal, disease-specific and health-related quality of life in patients with coronary artery disease, compared with an age- and gender-matched randomly selected group from the general population. Background. There are gender difference effects of sleep disturbances in the general population, but this perspective among patients with coronary artery disease has been poorly analysed. Design. In this prospective study, comparative, descriptive and model testing designs were used. Method. The patients with coronary artery disease, 556 men and 324 women aged 25–86, were compared with a matched population-based group. Data were collected by validated and reliability-tested questionnaires. Results. The prevalence of severe insomnia varied between 17–44% in all four groups. The severe insomniac coronary artery disease patients displayed a two- or threefold higher presleep arousal, had two hours shorter nocturnal sleep duration/night and were more limited in their physical exercise level than the population-based group. Gender differences in sleep quality, sleep efficiency (%) and general arousal disappeared with increased insomnia severity. Conclusions. Independent of gender, age and comorbidity, physical exercise, general arousal behaviour and delayed poststress recovery after mental stress were found to have a negative impact on the coronary artery disease patients’ sleep quality and sleep efficiency (%), interfering with their health-related quality of life. The variables significantly explained 41% of the sleep quality outcome and 29% of the sleep efficiency (%). Relevance to clinical practice. Insomnia because of hyperarousal behaviour can be an important factor in the development of an individual self-care management programme supported by a healthcare team.
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| 7. |
- Kristensson, Lisbeth, et al.
(författare)
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Plasminogen binding inhibitors demonstrate unwanted activities on GABAA and glycine receptors in human iPSC derived neurons
- 2018
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Ingår i: Neuroscience Letters. - : Elsevier. - 0304-3940 .- 1872-7972. ; 681, s. 37-43
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Tidskriftsartikel (refereegranskat)abstract
- Plasminogen binding inhibitors (PBIs) reduce the risk of bleeding in hemorrhagic conditions. However, generic PBIs are also associated with an increased risk of seizures, an adverse effect linked to unwanted activities towards inhibitory neuronal receptors. Development of novel PBIs serve to remove compounds with such properties, but progress is limited by a lack of higher throughput methods with human translatability. Herein we apply human induced pluripotent stem cell (hiPSC) derived neurons in combination with dynamic mass redistribution (DMR) technology to demonstrate robust and reproducible modulation of both GABAA and glycine receptors. These cells respond to GABA (EC50 0.33 ± 0.18 μM), glycine (EC50 11.0 ± 3.7 μM) and additional ligands in line with previous reports from patch clamp technologies. Additionally, we identify and characterize a competitive antagonistic behavior of the prototype inhibitor and drug tranexamic acid (TXA). Finally, we demonstrate proof of concept for effective counter-screening of lead series compounds towards unwanted GABAAreceptor activities. No activity was observed for a previously identified PBI candidate drug, AZD6564, whereas a discontinued analog, AZ13267257, could be characterized as a potent GABAA receptor agonist.
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| 8. |
- Labori, Knut Jørgen, et al.
(författare)
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Neoadjuvant FOLFIRINOX versus upfront surgery for resectable pancreatic head cancer (NORPACT-1) : a multicentre, randomised, phase 2 trial
- 2024
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Ingår i: The Lancet Gastroenterology & Hepatology. - : The Lancet Group. - 2468-1253. ; 9:3, s. 205-217
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundIn patients undergoing resection for pancreatic cancer, adjuvant modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) improves overall survival compared with alternative chemotherapy regimens. We aimed to compare the efficacy and safety of neoadjuvant FOLFIRINOX with the standard strategy of upfront surgery in patients with resectable pancreatic ductal adenocarcinoma.MethodsNORPACT-1 was a multicentre, randomised, phase 2 trial done in 12 hospitals in Denmark, Finland, Norway, and Sweden. Eligible patients were aged 18 years or older, with a WHO performance status of 0 or 1, and had a resectable tumour of the pancreatic head radiologically strongly suspected to be pancreatic adenocarcinoma. Participants were randomly assigned (3:2 before October, 2018, and 1:1 after) to the neoadjuvant FOLFIRINOX group or upfront surgery group. Patients in the neoadjuvant FOLFIRINOX group received four neoadjuvant cycles of FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin 400 mg/m2, and fluorouracil 400 mg/m2 bolus then 2400 mg/m2 over 46 h on day 1 of each 14-day cycle), followed by surgery and adjuvant chemotherapy. Patients in the upfront surgery group underwent surgery and then received adjuvant chemotherapy. Initially, adjuvant chemotherapy was gemcitabine plus capecitabine (gemcitabine 1000 mg/m2 over 30 min on days 1, 8, and 15 of each 28-day cycle and capecitabine 830 mg/m2 twice daily for 3 weeks with 1 week of rest in each 28-day cycle; four cycles in the neoadjuvant FOLFIRINOX group, six cycles in the upfront surgery group). A protocol amendment was subsequently made to permit use of adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m2, irinotecan 150 mg/m2, leucovorin 400 mg/m2, and fluorouracil 2400 mg/m2 over 46 h on day 1 of each 14-day cycle; eight cycles in the neoadjuvant FOLFIRINOX group, 12 cycles in the upfront surgery group). Randomisation was performed with a computerised algorithm that stratified for each participating centre and used a concealed block size of two to six. Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was overall survival at 18 months. Analyses were done in the intention-to-treat (ITT) and per-protocol populations. Safety was assessed in all patients who were randomly assigned and received at least one cycle of neoadjuvant or adjuvant therapy. This trial is registered with ClinicalTrials.gov, NCT02919787, and EudraCT, 2015-001635-21, and is ongoing.FindingsBetween Feb 8, 2017, and April 21, 2021, 77 patients were randomly assigned to receive neoadjuvant FOLFIRINOX and 63 to undergo upfront surgery. All patients were included in the ITT analysis. For the per-protocol analysis, 17 (22%) patients were excluded from the neoadjuvant FOLFIRINOX group (ten did not receive neoadjuvant therapy, four did not have pancreatic ductal adenocarcinoma, and three received another neoadjuvant regimen), and eight (13%) were excluded from the upfront surgery group (seven did not have pancreatic ductal adenocarcinoma and one did not undergo surgical exploration). 61 (79%) of 77 patients in the neoadjuvant FOLFIRINOX group received neoadjuvant therapy. The proportion of patients alive at 18 months by ITT was 60% (95% CI 49–71) in the neoadjuvant FOLFIRINOX group versus 73% (62–84) in the upfront surgery group (p=0·032), and median overall survival by ITT was 25·1 months (95% CI 17·2–34·9) versus 38·5 months (27·6–not reached; hazard ratio [HR] 1·52 [95% CI 1·00–2·33], log-rank p=0·050). The proportion of patients alive at 18 months in per-protocol analysis was 57% (95% CI 46–67) in the neoadjuvant FOLFIRINOX group versus 70% (55–83) in the upfront surgery group (p=0·14), and median overall survival in per-protocol population was 23·0 months (95% CI 16·2–34·9) versus 34·4 months (19·4–not reached; HR 1·46 [95% CI 0·99–2·17], log-rank p=0·058). In the safety population, 42 (58%) of 73 patients in the neoadjuvant FOLFIRINOX group and 19 (40%) of 47 patients in the upfront surgery group had at least one grade 3 or worse adverse event. 63 (82%) of 77 patients in the neoadjuvant group and 56 (89%) of 63 patients in the upfront surgery group had resection (p=0·24). One sudden death of unknown cause and one COVID-19-related death occurred after the first cycle of neoadjuvant FOLFIRINOX. Adjuvant chemotherapy was initiated in 51 (86%) of 59 patients with resected pancreatic ductal adenocarcinoma in the neoadjuvant FOLFIRINOX group and 44 (90%) of 49 patients with resected pancreatic ductal adenocarcinoma in the upfront surgery group (p=0·56). Adjuvant modified FOLFIRINOX was given to 13 (25%) patients in the neoadjuvant FOLFIRINOX group and 19 (43%) patients in the upfront surgery group. During adjuvant chemotherapy, neutropenia (11 [22%] patients in the neoadjuvant FOLFIRINOX group and five [11%] in the upfront surgery group) was the most common grade 3 or worse adverse event.InterpretationThis phase 2 trial did not show a survival benefit from neoadjuvant FOLFIRINOX in resectable pancreatic ductal adenocarcinoma compared with upfront surgery. Implementation of neoadjuvant FOLFIRINOX was challenging. Future trials on treatment sequencing in resectable pancreatic ductal adenocarcinoma should be biomarker driven.
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| 9. |
- Landegren, Nils, et al.
(författare)
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Transglutaminase 4 as a prostate autoantigen in male subfertility
- 2015
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science. - 1946-6234 .- 1946-6242. ; 7:292
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Tidskriftsartikel (refereegranskat)abstract
- Autoimmune polyendocrine syndrome type 1 (APS1), a monogenic disorder caused by AIRE gene mutations, features multiple autoimmune disease components. Infertility is common in both males and females with APS1. Although female infertility can be explained by autoimmune ovarian failure, the mechanisms underlying male infertility have remained poorly understood. We performed a proteome-wide autoantibody screen in APS1 patient sera to assess the autoimmune response against the male reproductive organs. By screening human protein arrays with male and female patient sera and by selecting for gender-imbalanced autoantibody signals, we identified transglutaminase 4 (TGM4) as a male-specific autoantigen. Notably, TGM4 is a prostatic secretory molecule with critical role in male reproduction. TGM4 autoantibodies were detected in most of the adult male APS1 patients but were absent in all the young males. Consecutive serum samples further revealed that TGM4 autoantibodies first presented during pubertal age and subsequent to prostate maturation. We assessed the animal model for APS1, the Aire-deficient mouse, and found spontaneous development of TGM4 autoantibodies specifically in males. Aire-deficient mice failed to present TGM4 in the thymus, consistent with a defect in central tolerance for TGM4. In the mouse, we further link TGM4 immunity with a destructive prostatitis and compromised secretion of TGM4. Collectively, our findings in APS1 patients and Aire-deficient mice reveal prostate autoimmunity as a major manifestation of APS1 with potential role in male subfertility.
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| 10. |
- Åkesson, Julia, et al.
(författare)
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Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.
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