| 1. |
- Gad, Helge, et al.
(författare)
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MTH1 inhibition eradicates cancer by preventing sanitation of the dNTP pool
- 2014
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 508:7495, s. 215-221
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Tidskriftsartikel (refereegranskat)abstract
- Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bindin the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
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| 2. |
- Holmberg, Marcus, et al.
(författare)
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Outcome after surgery for invasive intraductal papillary mucinous neoplasia compared to conventional pancreatic ductal adenocarcinoma : a swedish nationwide register-based study
- 2022
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Ingår i: Pancreatology (Print). - : Elsevier. - 1424-3903 .- 1424-3911. ; 23:1, s. 90-97
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Tidskriftsartikel (refereegranskat)abstract
- Background: The clinical importance of intraductal papillary mucinous neoplasm (IPMN) have increased last decades. Long-term survival after resection for invasive IPMN (inv-IPMN) compared to conventional pancreatic ductal adenocarcinoma (PDAC) is not thoroughly delineated.Objective: This study, based on the Swedish national pancreatic and periampullary cancer registry aims to elucidate the outcome after resection of inv-IPMN compared to PDAC.Methods: All patients ≥18 years of age resected for inv-IPMN and PDAC in Sweden between 2010 and 2019 were included. Clinicopathological variables were retrieved from the national registry. The effect on death was assessed in two multivariable Cox regression models, one for patients resected 2010–2015, one for patients resected 2016–2019. Median overall survival (OS) was estimated using the Kaplan-Meier method.Results: We included 1909 patients, 293 inv-IPMN and 1616 PDAC. The most important independent predictors of death in multivariable Cox regressions were CA19-9 levels, venous resection, tumour differentiation, as well as T-, N-, M-stage and surgical margin. Tumour type was an independent predictor for death in the 2016–2019 cohort, but not in the 2010–2015 cohort. In Kaplan-Meier survival analysis, inv-IPMN was associated with longer median OS in stage N0-1 and in stage M0 compared to PDAC. However, in stage T2-4 and stage N2 median OS was similar, and in stage M1 even shorter for inv-IPMN compared to PDAC.Conclusion: In this population-based nationwide study, outcome after resected inv-IPMN compared to PDAC is more favourable in lower stages, and similar to worse in higher.
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| 3. |
- Agerström, Jens, et al.
(författare)
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All else equal : Examining treatment bias and stereotypes based on patient ethnicity and socioeconomic status using in-hospital cardiac arrest clinical vignettes
- 2024
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Ingår i: Heart and Lung. - : MOSBY-ELSEVIER. - 0147-9563 .- 1527-3288. ; 63, s. 86-91
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Tidskriftsartikel (refereegranskat)abstract
- Background: Research on ethnic and socioeconomic treatment differences following in-hospital cardiac arrest (IHCA) largely draws on register data. Due to the correlational nature of such data, it cannot be concluded whether detected differences reflect treatment bias/discrimination – whereby otherwise identical patients are treated differently solely due to sociodemographic factors. To be able to establish discrimination, experimental research is needed. Objective: The primary aim of this experimental study was to examine whether simulated IHCA patients receive different treatment recommendations based on ethnicity and socioeconomic status (SES), holding all other factors (e.g., health status) constant. Another aim was to examine health care professionals’ (HCP) stereotypical beliefs about these groups. Methods: HCP (N = 235) working in acute care made anonymous treatment recommendations while reading IHCA clinical vignettes wherein the patient's ethnicity (Swedish vs. Middle Eastern) and SES had been manipulated. Afterwards they estimated to what extent hospital staff associate these patient groups with certain traits (stereotypes). Results: No significant differences in treatment recommendations for Swedish versus Middle Eastern or high versus low SES patients were found. Reported stereotypes about Middle Eastern patients were uniformly negative. SES-related stereotypes, however, were mixed. High SES patients were believed to be more competent (e.g., respected), but less warm (e.g., friendly) than low SES patients. Conclusions: Swedish HCP do not seem to discriminate against patients with Middle Eastern or low SES backgrounds when recommending treatment for simulated IHCA cases, despite the existence of negative stereotypes about these groups. Implications for health care equality and quality are discussed.
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| 4. |
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| 5. |
- Ehrstedt, Christoffer, et al.
(författare)
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Somatostatin receptor expression and mTOR pathway activation in glioneuronal tumours of childhood
- 2020
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Ingår i: Seizure. - : Elsevier BV. - 1059-1311 .- 1532-2688. ; 76, s. 123-130
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To investigate the expression of somatostatin receptors (SSTRs) and markers of mTOR pathway in paediatric glioneuronal tumours and correlate these findings with tumour type, BRAFV600E mutational status and clinical characteristics such as tumour location, seizure frequency and duration, and age.Method: 37 children and adolescents with a neuropathological diagnosis of glioneuronal tumour were identified over a 22-year period. Immunohistochemical analyses for SSTRs type 1, 2A, 3, 5 and ezrin-radixin-moesin (ERM) and phosphorylated S6 (pS6), which are indicators of mTOR pathway activation, were performed in tumour specimens from 33 patients and evaluated using the immunoreactive score (IRS). The IRS were compared to tumour type, BRAFV600E status and clinical characteristics.Results: Ganglioglioma (GG) was the most frequently encountered subgroup (n = 27), followed by dysembryoplastic neuroepithelial tumour (DNET; n=4). GGs expressed SSTR2A and SSTR3 to a high extent, 56 % and 44 % respectively. Expression of SSTR2A was also found in DNETs. Signs of mTOR pathway activation were abundant in GGs, but only present in one DNET. No correlations with BRAFV600E presence or clinical characteristics were found.Conclusions: Expression of SSTRs and activation of mTOR pathway in paediatric glioneuronal tumour suggest that somatostatin analogues and mTOR inhibitors may have potential therapeutic implications in a subset of inoperable childhood glioneuronal tumours causing medically refractory epilepsy and/or tumour growth. Further clinical studies are warranted to validate these findings.
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| 6. |
- Frühling, Petter, et al.
(författare)
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A comparison of the simultaneous, liver-first, and colorectal-first strategies for surgical treatment of synchronous Colorectal Liver Metastases at two major liver-surgery institutions in Sweden
- 2023
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Ingår i: HPB. - : Elsevier. - 1365-182X .- 1477-2574. ; 25:1, s. 26-36
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe optimal treatment strategy for patients with synchronous colorectal liver metastases is unclear. The aim of this study was to compare the outcome of the simultaneous, liver-first, and colorectal-first surgical approaches. MethodsAll consecutive patients with synchronous colorectal liver metastases who underwent liver resection with curative intent were included. Data were collected from local databases. Patient and tumour specific characteristics were retrieved, and clinicopathological factors were analysed. A Cox regression model was constructed, and a subgroup intention-to-treat analysis was performed after propensity score matching. ResultsA total of 658 patients were included in the analysis. Ninety-two patients had a simultaneous resection, 163 patients had liver-first, and 403 patients had a colorectal-first approach. After matching, two balanced groups between the simultaneous and liver-first groups were created with 58 patients in each. There were no differences in post-operative complications defined as Clavien-Dindo 3a (p=0.992), and >3a (p=0.999). There were no differences in overall survival between the groups (stratified log rank p=0.455). The median overall survival for liver-first was 42.2 (26.3-58.2) months, and for the simultaneous groups, 56.2 (47.1-65.4). ConclusionThe simultaneous approach was not associated with worse overall survival compared to a staged approach, and had comparable morbidity and mortality.
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| 7. |
- Frühling, Petter, et al.
(författare)
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The prognostic value of C-reactive protein and albumin in patients undergoing resection of colorectal liver metastases. A retrospective cohort study
- 2021
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Ingår i: HPB. - : Elsevier. - 1365-182X .- 1477-2574. ; 23:6, s. 970-978
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The systemic inflammation-based Glasgow Prognostic Score (GPS) and modified GPS (mGPS), as measured by preoperative C-reactive protein (CRP) and albumin, correlate with poor survival in several cancers. This study evaluates the prognostic value of these scores in patients with colorectal liver metastases (CRLM).METHODS: This retrospective study assessed the prognostic role of preoperatively measured GPS and mGPS in patients undergoing liver resection because of CRLM. Clinicopathological data were retrieved from local databases. The prognostic value of GPS and mGPS were compared and a Cox regression model was used to find independent predictors of overall survival.RESULTS: In total, 849 consecutive patients between January 2005 and December 2015 were included. Patients with GPS 0 had a median survival of 70 months compared to 49 months in patients with GPS 1, and 27 months in patients with GPS 2. Multivariable analyses showed that GPS 1 (HR = 1.51, 95%CI [1.14-2.01]) and GPS 2 (HR = 2.78, 95%CI [1.79-4.31]), after correction for age >70 years (HR = 1.75 [1.36-2.26]), and extended resection (HR = 2.53, 95%CI[1.79-3.58]), were associated with poor overall survival.CONCLUSION: A preoperative GPS is an independent prognostic factor in patients with CRLM, and appears to be a better prognostic tool than mGPS.
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| 8. |
- Gilg, Stefan, et al.
(författare)
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The impact of post-hepatectomy liver failure on mortality : a population-based study
- 2018
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 53:10-11, s. 1335-1339
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Tidskriftsartikel (refereegranskat)abstract
- Background: Post-hepatectomy liver failure (PHLF) is considered a main reason for death after major hepatectomy. The reported PHLF-related mortality differs largely and the data mainly originate from single centers.Aim: A retrospective, population-based register study was designed to evaluate the impact of PHLF on 90-day mortality after hepatectomy.Method: All patients who underwent liver resection in Sweden between 2005 and 2009 were retrospectively identified using the Swedish Hospital Discharge Registry. 30- and 90-day mortality were identified by linkage to the Registry of Causes of Death. Additional clinical data were obtained from the medical charts in all seven university hospitals in Sweden. PHLF was defined according to Balzan criteria (Bilirubin >50 µg/L and international normalized ratio >1.5) on postoperative day 5.Results: A total of 2461 liver resections were performed (2194 in university hospitals). 30- and 90-day mortality were 1.3% and 2.5%, respectively. 90-day mortality at university hospitals was 2.1% (n = 46). In 41% (n = 19) of these patients, PHLF alone or in combination with multi-organ failure was identified as cause of death. Between the PHLF and non-PHLF group, there was no significant difference regarding age, sex, American Society of Anesthesiologists-classification, or preoperative chemotherapy. Cholangiocarcinoma as indication for surgery, need for vascular reconstruction and an extended resection were significantly overrepresented in the PHLF-group. Between groups, the incidence of 50:50 criteria differed significantly already on postoperative day 3.Conclusion: Overall mortality is very low after hepatectomy in Sweden. PHLF represents the single most important cause of death even in a population-based setting.
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| 9. |
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| 10. |
- Katzeff, Cecilia, Associate professor, 1957-, et al.
(författare)
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TRUSTnEnergy : Sociala aspekter på tillit till automatisering i framtidens energisystem
- 2022
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Rapport (populärvet., debatt m.m.)abstract
- Rapporten utgör slutredovisning av förstudien TRUSTnEnergy, som utforskar betydelsen av tillit i relation till hushållens roll i smarta elnät, med särskilt fokus på automatisering. Fokus i projektet är tillitens i förhållande till automatiseringen av elsystemet och hur den berör elanvändning i våra hem. Syftet är att belysa vilken roll tillit spelar i relation till hushållens roll i smarta elnät, med särskilt fokus på automatisering för styrning av elanvändning. Studien består av tre delar: En litteraturstudie av forskning om hushållens tillit till smarta elnät; en litteraturstudie av forskning om tillit till automatiserade fordon; samt en intervjustudie av aktörer inom automatisering av elnätet och hushåll som har automatisering i sin bostad.I forskningslitteraturen om hushållens tillit identifierades tre typer av risker – ekonomiska risker, förlorad kontroll och säkerhets-/integritetsrisker – som hushåll upplevde i samband med ny, automatiserad teknik kopplade till elsystemet i hemmet. Konsekvenser av hög tillit till aktörer bakom systemen som lyfts i litteraturen är t.ex. ökad acceptans för systemen, minskad oro för risker och att hushåll ser fler fördelar med tekniken. Låg tillit kan tvärtom göra hushåll mer negativt inställda och kan påverka viljan att testa nya produkter och tjänster, även om ekonomiska aspekter väger tyngre.Den växande forskningslitteraturen om tillit till automatiserade fordon ger kunskap som kan överföras på människors tillit till smarta elnät. Här finns en omfattande modell av faktorer som påverkar hur tillit byggs upp, och som får mer och mer inflytande på forskningen. De pekar på tre olika former av tillit som tillsammans bygger hur mycket användaren i slutändan väljer att lita på automationen. Resultaten från intervjustudien visar att aktörerna tror att den största nyttan som hushållen kommer att uppleva i närtid är en ekonomisk nytta för den automatiserade elanvändningen. En annan nytta som hushållen förutspås kunna erfara är den ökade komforten som det intelligenta hemmet kan ge. Risker och problem som hushållen skulle kunna uppleva är sådana som har att göra med den ökande komplexiteten i systemet, teknik som fallerar, datasäkerhet och bristande kompetens hos leverantörer och husägare. Hushållen ser ekonomi som den största nyttan. Risker och problem förknippas starkast med bristen på transparens, komplexitet, datasäkerhet och bristande kommunikation med leverantörer. Resultaten från förstudien pekar på en rad kunskapsluckor om vad som bestämmer hushållens tillit till smarta elnät och automatisering av sina hem. Här finns intressanta spår att följa och studier i verkliga miljöer att utföra.
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| 11. |
- Larsson, Glenn, et al.
(författare)
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Cognitive status following a hip fracture and its association with postoperative mortality and activities of daily living : A prospective comparative study of two prehospital emergency care procedures
- 2019
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Ingår i: International Journal of Orthopaedic and Trauma Nursing. - : Elsevier BV. - 1878-1241.
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Early assessment of hip fracture patients’ cognitive function is important for preventing pre- and postoperative complications. The aim of this study was twofold: (1) to assess prehospital cognitive function in hip fracture patients and establish whether cognitive status differs pre- and postoperatively between prehospital fast track care (PFTC) and the traditional emergency department (ED) pathway and (2) whether preoperative cognitive function is associated with postoperative mortality and activities of daily living (ADL) ability. Methods: Three hundred and ninety one hip fracture patients were prospectively included. The Short Portable Mental Status Questionnaire (SPMSQ) was used prehospital, at the orthopaedic ward and three days postoperatively. ADL was followed up after four months. Results: No difference in patients’ cognitive function was observed between PFTC and ED. Four-month mortality was 37% for patients with dementia, 21% for those with cognitive impairment and 10% for patients without cognitive impariment. Only 26% of patients with dementia and 47% with cognitive impairment had full ADL ability, compared with 70% of patients with intact cognitive function (p < 0.001). Conclusion: PFTC did not influence hip fracture patients’ cognitive function. Patients with prehospital cognitive impairment had a poor outcome in terms of mortality and ADL, indicating the need for special care interventions.
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| 12. |
- Larsson, Glenn, et al.
(författare)
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It was not a hip fracture - you were lucky this time - or perhaps not! A prospective study of clinical outcomes in patients with low-energy pelvic fractures and hip contusions
- 2019
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Ingår i: Injury-International Journal of the Care of the Injured. - : Elsevier BV. - 0020-1383. ; 50:4, s. 913-918
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Prehospital and hospital emergency care guidelines have been developed for patients with suspected hip fracture. Initial radiography can identify a number of patients with other injuries, generally pelvic fractures and hip contusions. Little is known about the prognosis for these patients. The aim of this study is twofold: i) to investigate the injury pattern of patients assessed in prehospital emergency care as suffering from a suspected hip fracture and ii) to compare clinical outcomes between patients with verified hip fracture (HF) and those with other hip injuries (OHI). Method: The study design was prospective. Older patients with suspected HF after low-energy trauma were identified in prehospital emergency care. Injury type was determined by radiological imaging. Comparisons of length of stay, adverse events, repeated prehospital emergency care and mortality were made between verified HF and OHI cases. Results: 449 patients were included, 400 in the HF and 149 in the OHI group (86 hip contusions, 46 pelvic fractures and 17 other injuries/diseases). The HF group had a significantly longer hospital stay (9.5 days vs. 6.3 for the OHI group; p < 0.001) and more adverse events while in hospital (34% vs. 19%; p < 0.001). We found no evidence that the groups differed with regard to other outcomes: mortality during hospital stay (4% vs. 2%, p = 0.42), at 4 (16% vs. 13%; p = 0.35) and 12 months (21 vs. 23%; p = 0.64), the proportion that experienced an adverse event (24% vs. 22%; p = 0.65) and the proportion that required another ambulance transport within 6 months after discharge (40% vs. 34%; p = 0.16). The results were not strongly affected by adjustments for possible confounders. Conclusion: Older patients who suffer a low-energy pelvic fracture or a hip contusion are common in prehospital and hospital emergency care. These patients need attention as they have poor outcomes in terms of adverse events, mortality and recurrent need for ambulance transport after discharge from hospital. While individualized multidisciplinary care is recommended for hip fracture patients, it might also be suitable for other geriatric hip injuries. (C) 2019 Elsevier Ltd. All rights reserved.
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| 13. |
- Larsson, Glenn, et al.
(författare)
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Patient satisfaction with prehospital emergency care following a hip fracture : A prospective questionnaire-based study
- 2018
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Ingår i: BMC Nursing. - : Springer Science and Business Media LLC. - 1472-6955. ; 17:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Older patients with a hip fracture require specialized emergency care and their first healthcare encounter before arriving at the hospital is often with the ambulance service. Since 2005 there has been a registered nurse on the crew of every ambulance in Sweden in order to provide prehospital emergency care and to prepare the patients for hospitalization. It is important to investigate patient satisfaction with prehospital emergency care following a hip fracture to ensure that their expectations of good care are met. The aim of this study was to investigate patient satisfaction with prehospital emergency care following a hip fracture by comparing two similar emergency care contexts. Methods: The study was conducted using the Consumer Emergency Care Satisfaction Scale (CECSS) on patients treated for hip fracture in prehospital emergency care. The data were collected within a randomized controlled study for the purpose of comparing prehospital fast track care (PFTC) and the traditional type of transport to an accident and emergency department (A&E). Results: Questionnaire data from 287 patients, 188 women (66%) and 99 men (34%) with a mean age of 80.9years, were analysed. More than 80% of the patients selected the most positive response alternatives, but 16% were dissatisfied with the nursing information provided. Patients in PFTC responded more positively on specific caring behaviour than those transported to the A&E department in the traditional way. Conclusion: Patient satisfaction with prehospital emergency care following a hip fracture is an important outcome and this study highlights the fact that patients expressed a high level of satisfaction with the prehospital emergency care provided by ambulance nurses in both care contexts under study. However, some areas need to be improved in terms of nursing information.
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| 14. |
- Larsson, Glenn, et al.
(författare)
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Prehospital fast track care for patients with hip fracture: Impact on time to surgery, hospital stay, post-operative complications and mortality a randomised, controlled trial.
- 2016
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Ingår i: Injury. - : Elsevier BV. - 1879-0267 .- 0020-1383.
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Tidskriftsartikel (refereegranskat)abstract
- Ambulance organisations in Sweden have introduced prehospital fast track care (PFTC) for patients with suspected hip fracture. This means that the ambulance nurse starts the pre-operative procedure otherwise implemented at the accident & emergency ward (A&E) and transports the patient directly to the radiology department instead of A&E. If the diagnosis is confirmed, the patient is transported directly to the orthopaedic ward. No previous randomised, controlled studies have analysed PFTC to describe its possible advantages. The aim of this study is to examine whether PFTC has any impact on outcomes such as time to surgery, length of stay, post-operative complications and mortality.
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| 15. |
- Ljung Faxen, Ulrika, et al.
(författare)
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N-terminal pro-B-type natriuretic peptide in chronic heart failure: The impact of sex across the ejection fraction spectrum
- 2019
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Ingår i: International Journal of Cardiology. - : ELSEVIER IRELAND LTD. - 0167-5273 .- 1874-1754. ; 21, s. 225-225
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim was to assess sex-specific differences in N-terminal B-type natriuretic peptide (NT-proBNP) regarding concentrations, predictors of high concentrations, and prognostic role, in a large and unselected population with chronic heart failure (HF) with preserved (HFpEF), mid-range (HFmrEF), and reduced ejection fraction (HFrEF). Methods and results: In 9847 outpatients with HFpEF, HFmrEF, and HFrEF (49 vs. 35 vs. 25% females, respectively) from the Swedish HF Registry, median NT-proBNP concentrations were 1598 ng/L in females vs. 1310 ng/L in males in HFpEF, 1764 vs. 1464 ng/L in HFmrEF, and 2543 vs. 2226 ng/L in HFrEF (p amp;lt; 0.05 for all). The differences persisted after multiple adjustment. The largest sex-difference in NT-proBNP levels was observed in HFpEF with sinus rhythm, where median concentrations were 1.4 folds higher in females (923 vs. 647 ng/L). Independent predictors of NT-proBNP levels (defined as above the different medians according to sex and HF phenotype) were overall consistent across sexes and EF. NT-proBNP levels were similarly associated with risk of all-cause death/HF hospitalization in both sexes regardless of EF. Conclusion: Concentrations of NT-proBNPwere higher in females across the EF spectrum, with larger relative differences in HFpEF with sinus rhythm. However, similar predictors of high levels were observed in both sexes. There were no sex-differences in the prognostic role of NT-proBNP. These findings support the use of NT-proBNP for prognostic purposes in chronic HF, regardless of sex. (c) 2019 Elsevier B.V. All rights reserved.
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| 16. |
- Lubking, Anna, et al.
(författare)
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Allogeneic stem cell transplantation for chronic myeloid leukemia in the TKI era : population-based data from the Swedish CML registry
- 2019
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Ingår i: Bone Marrow Transplantation. - : Springer Science and Business Media LLC. - 0268-3369 .- 1476-5365. ; 54:11, s. 1764-1774
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Tidskriftsartikel (refereegranskat)abstract
- Two decades after the introduction of tyrosine kinase inhibitors (TKI), a sizeable portion of patients with chronic myeloid leukemia (CML) in chronic phase (CP) still undergo allogeneic stem cell transplantation (allo-HSCT). We investigated the indications for allo-HSCT, clinical outcome, management of relapse, and post-transplant TKI treatment in a population-based setting using the Swedish CML registry. Of 118 CML patients transplanted between 2002 and 2017, 56 (47.4%) received allo-HSCT in first CP, among whom TM resistance was the most common transplant indication (62.5%). For patients diagnosed with CML in CP at <65 years of age, the cumulative probability of undergoing allo-HSCT within 5 years was 9.7%. Overall 5-year survival was 96.2%, 70.1% and 36.9% when transplanted in first CP, second or later CP, and in accelerated phase or blast crisis, respectively. Risk factors for relapse were EBMT score >2 and reduced intensity conditioning, and for death, CP > 2 at time point of allo-HSCT only. Non-relapse mortality for patients transplanted in CP was 11.6%. Our data indicate that allo-HSCT still constitutes a reasonable therapeutic option for patients with CML in first CP, especially those resistant to TKI treatment, providing high long-term survival and low non-relapse mortality.
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| 17. |
- Marschinke, Franziska, 1978-
(författare)
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From dopamine nerve fiber formation to astrocytes
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Parkinson’s disease (PD) is a progressive neurodegenerative disease and characterized by the loss of dopaminergic (DA) neurons in the substantia nigra in the midbrain. The causes of the disease are still unknown. The most commonly used treatment is administration of L-DOPA, however, another possible treatment strategy is to transplant DA neurons to the striatum of PD patients to substitute the loss of neurons. Clinical trials have demonstrated beneficial effects from transplantation, but one obstacle with the grafting trials has been the variable outcome, where limited graft reinnervation of the host brain is one important issue to solve. To improve and control the graft DA nerve fiber outgrowth organotypic tissue cultures can be utilized. Cultures of fetal ventral mesencephalon (VM) have been used to investigate astrocytic migration and dopamine nerve fiber formations at different time points and under varying conditions to study how to control nerve fiber formation. The early appearing DA nerve fibers as revealed by tyrosine hydroxylase (TH) –immunoreactivity, form their fibers in the absence of glial cell bodies, are not persistent over time, and is called non-glial-associated TH-positive nerve fiber outgrowth. A monolayer of astrocytes guides a second persistent subpopulation of nerve fibers, the glial-associated TH-positive nerve fiber formation. Investigations of the interactions between the astrocytic migration and nerve fiber formations were made. In embryonic (E) day 14 VM cultures the mitosis of the astrocytes was inhibited with the antimitotic agent β-D-arabinofuranoside. The results revealed decreased astrocytic migration, reduced glial-associated TH-positive outgrowth, and enhanced presence of the non-glial-associated TH-positive outgrowth in the cultures. Thus, astrocytes affect both the non-glial- and the glial-associated growths by either its absence or presence, respectively. The astrocytes synthesize proteoglycans. Therefore the nerve fiber formation was studied in VM or spinal cord cultures treated with the proteoglycan blockers chondroitinase ABC (ChABC), which degrades the proteoglycans, or methyl-umbelliferyl-β-D-xyloside (β-xyloside), which blocks the proteoglycan synthesis. β-xyloside inhibited the migration of the astrocytes and the outgrowth of the glial-associated TH-positive nerve fibers in both VM and spinal cord cultures, whereas ChABC treatment had no effect in E14 VM or spinal cord cultures. E18 VM and spinal cord cultures were evaluated to investigate how the different developmental stages influence astrocytes and the two nerve fiber formations after 14 DIV. No nerve fiber formation was found in E18 VM cultures, while the non-glial-associated nerve fiber outgrowth was obvious as long and robust fibers in E18 spinal cord cultures. The astrocytic migration was similar in VM and spinal cord cultures. β-xyloside and ChABC did not affect nerve fiber growth but astrocytic migration in E18 VM cultures, while no effects was found in the spinal cord cultures. However, the neuronal migration found in control cultures was abolished in both VM and spinal cord cultures after both ChABC and β-xyloside. Neuroinflammation plays a critical role in the development of PD. Increased levels of the proinflammatory cytokine tumor necrosis factor alpha (TNFα) are observed in postmortem PD brains and the levels of TNFα receptors on circulating T-lymphocytes in cerebrospinal fluid of PD patients are increased. The effects of TNFα were studied on E14 VM cultures. The outgrowth of the non-glial-associated TH-positive nerve fibers was inhibited while it stimulated astrocytic migration and glial-associated TH-positive nerve fiber outgrowth at an early treatment time point. Furthermore, blocking the endogenous levels of TNFα resulted in cell death of the TH-positive neurons. Furthermore, cultures of E14 mice with gene deletion for the protein CD47 were investigated. CD47 is expressed in all tissues and serves as a ligand for the signal regulatory protein (SIRP) α, which promotes e.g migration and synaptogenesis. CD47-/- cultures displayed massive and long non-glial-associated TH-positive nerve fiber outgrowth despite a normal astrocytic migration and the presence of glial-associated TH-positive nerve fiber outgrowth. For the first time, it was observed that the non-glial-guided TH-positive nerve fiber outgrowth did not degenerate after 14 DIV. Taken together, there is an interaction between astrocytes and TH-positive nerve fiber formations. Both nerve fiber formations seem to have their task during the development of the DA system.
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| 18. |
- Montgomery, Cecilia, et al.
(författare)
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The Structured Observation of Motor Performance in Infants can detect cerebral palsy early in neonatal intensive care recipients
- 2017
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Ingår i: Early Human Development. - : Elsevier BV. - 0378-3782 .- 1872-6232. ; 113, s. 31-39
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe detection of motor problems in infancy requires a detailed assessment method that measures both the infants' level of motor development and movement quality.AimTo evaluate the ability of the Structured Observation of Motor Performance in Infants (SOMP-I) to detect cerebral palsy (CP) in neonatal intensive care recipients.Study designProspective cohort study analyzed retrospectively.Subjects212 (girls: 96) neonatal intensive care recipients (mean gestational age 34 weeks, range: 23–43). Twenty infants were diagnosed with CP.Outcome measuresThe infants were assessed using SOMP-I at 2, 4, 6 and 10 months' corrected age. Accuracy measures were calculated for level of motor development, quality of motor performance and a combination of the two to detect CP at single and repeated assessments.ResultsAt 2 months, 17 of 20 infants with CP were detected, giving a sensitivity of 85% (95% CI 62–97%) and a specificity of 48% (95% CI 40–55%), while the negative likelihood ratio was 0.3 (95% CI 0.1–0.9) and the positive likelihood ratio was 1.6 (95% CI 1.3–2.0). At 6 months all infants with CP were detected using SOMP-I, and all infants had repeatedly been assessed outside the cut-offs. Specificity was generally lower for all assessment ages, however, for repeated assessments sensitivity reached 90% (95% CI 68–99%) and specificity 85% (95% CI 79–90%).ConclusionsSOMP-I is sensitive for detecting CP early, but using the chosen cut-off can lead to false positives for CP. Assessing level and quality in combination and at repeated assessments improved predictive ability.
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| 19. |
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| 20. |
- Ragnarsson, Lotten, et al.
(författare)
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Multiple myeloma cells are killed by syndecan-1-directed superantigen-activated T cells
- 2001
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 50:7, s. 382-390
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Tidskriftsartikel (refereegranskat)abstract
- Multiple myeloma (MM) is an incurable plasma cell/plasmablast malignancy with a great need for innovative treatment strategies. Since experimental immunotherapy with targeted superantigens (SAg) proved to be effective in other haematopoietic tumours, we investigated whether this would also hold true for MM. We used the bacterial SAg Staphylococcus enterotoxin A (SEA), a potent activator of T cell cytotoxicity by means of its binding to particular T cell receptor Vbeta sequences on effector cells and MHC class II molecules on target cells. To eliminate potentially unspecific binding via MHC class II, SEA was point mutated (SEAm). In a second step SEAm was genetically fused to protein A (PA), resulting in a fusion protein (PA-SEAm). This fusion protein was used together with four different plasma-cell-specific/associated mAbs to direct T cells towards 10 MM target cell lines. Three of these mAbs were directed against syndecan-1/CD138, known to be highly expressed on MM and plasma cells, but absent on other haematopoietic cells. All MM cell lines proved to be sensitive to SAg-activated T cell killing (15-50% lysis), as measured in a 51Cr-release assay. This effect was clearly mediated via the plasma-cell-reactive antibodies, as control antibodies only conferred a low background lysis. MM therapy based on targeted SAgs could in theory be hampered by dysfunctional T cells in MM patients. However, we show that T cells from MM patients and healthy controls responded equally well to activation by SAg.
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| 21. |
- Ryner, Martin, et al.
(författare)
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Identification and classification of human cytomegalovirus capsids in textured electron micrographs using deformed template matching
- 2006
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Ingår i: Virology Journal. - : Springer Science and Business Media LLC. - 1743-422X. ; 3
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Tidskriftsartikel (refereegranskat)abstract
- Background: Characterization of the structural morphology of virus particles in electron micrographs is a complex task, but desirable in connection with investigation of the maturation process and detection of changes in viral particle morphology in response to the effect of a mutation or antiviral drugs being applied. Therefore, we have here developed a procedure for describing and classifying virus particle forms in electron micrographs, based on determination of the invariant characteristics of the projection of a given virus structure. The template for the virus particle is created on the basis of information obtained from a small training set of electron micrographs and is then employed to classify and quantify similar structures of interest in an unlimited number of electron micrographs by a process of correlation. Results: Practical application of the method is demonstrated by the ability to locate three diverse classes of virus particles in transmission electron micrographs of fibroblasts infected with human cytomegalovirus. These results show that fast screening of the total number of viral structures at different stages of maturation in a large set of electron micrographs, a task that is otherwise both time-consuming and tedious for the expert, can be accomplished rapidly and reliably with our automated procedure. Using linear deformation analysis, this novel algorithm described here can handle capsid variations such as ellipticity and furthermore allows evaluation of properties such as the size and orientation of a virus particle. Conclusion: Our methodological procedure represents a promising objective tool for comparative studies of the intracellular assembly processes of virus particles using electron microscopy in combination with our digitized image analysis tool. An automated method for sorting and classifying virus particles at different stages of maturation will enable us to quantify virus production in all stages of the virus maturation process, not only count the number of infectious particles released from un infected cell.
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| 22. |
- Sternby Eilard, Malin, 1974, et al.
(författare)
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Survival and prognostic factors after transplantation, resection and ablation in a national cohort of early hepatocellular carcinoma
- 2021
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Ingår i: HPB. - : Elsevier BV. - 1365-182X .- 1477-2574. ; 23:3, s. 394-403
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Tidskriftsartikel (refereegranskat)abstract
- © 2020 International Hepato-Pancreato-Biliary Association Inc. Background: In patients with early hepatocellular cancer (HCC) and preserved liver function, the choice between transplantation, resection and ablation and which factors to consider is not obvious and guidelines differ. In this national cohort study, we aimed to compare posttreatment survival in patients fulfilling predefined criteria, and to analyse preoperative risk factors that could influence decision. Methods: We used data from HCC-patients registered with primary transplantation, resection or ablation 2008–2016 in the SweLiv-registry. In Child A-subgroups, 18–75 years, we compared survival after transplantation or resection, with different tumour criteria; either corresponding to our transplantation criteria (N = 257) or stricter with single tumours ≤50 mm (N = 159). A subgroup with single tumours ≤30 mm, compared all three treatments (N = 193). Results: We included 1022 HCC-patients; transplantation n = 223, resection n = 438, ablation n = 361. In the transplant criteria subgroup, differences in five-year survival, adjusted for age and gender, were not significant, with 71.2% (CI 62.3–81.3) after transplantation (n = 109) and 63.5% (CI 54.9–73.5) after resection (n = 148). Good liver function (Child 5 vs. 6, Albumin ≥36), increased the risk after transplantation, but decreased the risk after resection and ablation. Conclusion: Even within Child A, detailed liver function assessment is important before treatment decision, and for stratifying survival comparisons.
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| 23. |
- Strömberg, Cecilia
(författare)
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Aspects of treatment of common bile duct stones
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Gallstone disease is a major cause of morbidity and at least 10 000 cholecystectomies are performed annually in Sweden. At the time of surgery about 5-15% of the patients also have common bile duct stones (CBDS). Introduction of new techniques like Endoscopic Retrograde CholangioPancreatography (ERCP) and laparoscopy have changed the treatment for these patients. Aims: To analyze how CBDS has been treated in Sweden 1965-2009 and to calculate mortality connected to the different procedures, to assess the risk of malignancy after ERCP in benign disease and identify risk factors for death within 90 days. To evaluate the short term clinical outcome and identify risk-factors for failure in laparoscopic transcystic common bile duct exploration (LTCE). Methods: Data on all patients with an in-patient procedure code of common bile duct exploration or ERCP 1965- 2009 were collected from the Swedish Hospital Discharge Register and those with a diagnosis of malignancy in the bile ducts, liver or pancreas were excluded. The outcome death was identified by cross-linkage to the Registry of Causes of Death and readmission in the Swedish Hospital Discharge Register. For assessment of cancer risk a cohort study of all patients in Sweden having had an ERCP before the end of 2003 without a diagnosis of malignancy at the time of the procedure or within two years after it was performed. To calculate mortality and analyze risk-factors for death after ERCP a case-control study based on the population of Stockholm 1990-2003 was performed. Cases were defined as patients having died within 90 days of the procedure and controls were randomly chosen among those who did not die. Data were collected prospectively on patients having a cholecystectomy at S:t Göran’s Hospital 1994-2002, in 155 patients a LTCE were attempted and the outcome analyzed. Results: The Swedish Hospital Discharge Registry contained records of 126 885 procedures for treatment of common bile duct stones in 110 119 individuals, without a diagnosis of malignancy at the time of the procedure, during 1965-2009. The 90-day mortality was 0.24 % after open surgery, 0.90% after ERCP, 0.67% after combined procedures and 0% after laparoscopic surgery. After adjustment for confounding factors, mainly age and comorbidity, in the multivariate analyses there was no significant difference in mortality between open surgery and ERCP. The risk of malignancy in the bile ducts alone and in the bile ducts, liver and pancreas together was significantly elevated in the cohort of individuals having had an ERCP before 2003, irrespective of if an ES was performed or not. The risk of malignancy diminished with increasing follow-up time. Patients ever having had a cholecystectomy had a significantly lower risk of the studied malignancies. In Stockholm County during 1990-2003 the 90-day mortality after ERCP was 1.6%. Advanced age, severe comorbidity, high complexity of the procedure and the occurrence of a complication were associated to death within 90 days, whereas a previous cholecystectomy or the simultaneous performance of an endoscopic sphincterotomy reduced the risk. An attempt of transcystic CBD exploration with complete stone clearance in the 155 patients at S:t Göran’s Hospital could be fulfilled in 85 %. The median operating time was 184 minutes (range 89-384 minutes) and the median postoperative hospital stay was one day. There was a significant 3-fold increase in risk of failure of clearance of the bile ducts among patients with stones of >5 mm compared to patients with stones ≤5 mm. Conclusions: Common bile duct stones were mainly treated endoscopically. ERCP and open surgery were associated with a similar mortality after adjustment for confounding factors. Laparoscopic treatment was chosen in younger and healthier patients, probably with a less severe disease, and no 90-day mortality was recorded. The risk of malignancy in the bile ducts, liver or pancreas was elevated after ERCP in benign disease. However, ES did not seem to affect this risk. Old age and comorbidity were the main risk factors for death after ERCP but a complex procedure or the occurrence of a complication also seemed to increase short term mortality. The performance of a sphincterotomy may decrease the risk of death, possibly by facilitating adequate drainage. Previous cholecystectomy may also decrease the risk of dying after ERCP. Laparoscopic transcystic exploration of the CBD had a high frequency of stone clearance and low morbidity in the present study. Moreover, large stones were a risk factor for failure in stone clearance.
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| 24. |
- Strömberg, Cecilia, et al.
(författare)
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Possible mortality reduction by endoscopic sphincterotomy during endoscopic retrograde cholangiopancreatography : a population-based case-control study.
- 2012
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Ingår i: Surgical Endoscopy. - : Springer Science and Business Media LLC. - 0930-2794 .- 1432-2218. ; 26:5, s. 1369-76
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) is widely used for young patients, but ERCP and endoscopic sphincterotomy in particular are reported to be associated with increased complication and mortality rates. This study aimed to calculate mortality and to identify risk factors for death within 90 days after ERCP for nonmalignant disease.METHODS: From the Swedish Hospital Discharge Registry, the authors identified all individuals in Stockholm County who had undergone in-patient ERCP during 1990-2003. Among these individuals, they excluded those recorded in the Swedish Cancer Registry as having a diagnosis of malignancy in the liver, pancreas, or bile ducts. Cases, defined as patients who had died within 90 days after the procedure, were identified by cross-linkage to the causes of death registry. Control subjects were randomly sampled from the same cohort. The medical records were studied to discern risk factors for death after ERCP.RESULTS: The mortality rate was 1.6%. Advanced age, severe comorbidity, high complexity of the procedure, and occurrence of a complication were associated with death within 90 days, whereas a previous cholecystectomy or the simultaneous performance of an endoscopic sphincterotomy reduced the risk.CONCLUSIONS: Old age and comorbidity are the main risk factors for death after ERCP, but a complex procedure or the occurrence of a complication also seems to increase short-term mortality. The performance of a sphincterotomy may reduce the risk of death, possibly by facilitating adequate drainage. A previous cholecystectomy also may decrease the risk of death after ERCP.
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| 25. |
- Strömberg, Helena, 1985, et al.
(författare)
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A future without drivers? Comparing users', urban planners' and developers' assumptions, hopes, and concerns about autonomous vehicles
- 2021
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Ingår i: European Transport Research Review. - : Springer Science and Business Media LLC. - 1867-0717 .- 1866-8887. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Aim: This study identifies and compares perceptions of autonomous vehicle (AV) implementation among three Swedish stakeholder groups: Future Users, Urban Planners, and Developers. Method: Semi-structured comparative focus groups were conducted separately with each of the three groups of stakeholders and the transcripts were analysed in broad themes using thematic analysis. Results: Assumptions, hopes, concerns, and direction of development were the main themes that emerged from the analysis. Assumptions included electrification of vehicles, changes in travel demand, and the need for regulations; Hopes included the idea that AVs will contribute to a more accessible and safer transport system; Concerns included overtrust in AV technology, a possible detrimental impact on the city in the form of congestion and higher demand for investments in infrastructure that could outcompete other modes of transport; and Direction of development and their own role, where the need for collaboration between stakeholders and implementation of AVs in connection with society’s needs were emphasised. Conclusions: AVs were seen to lead to both positive and negative consequences depending on implementation and the development of society. The study shows that dialogue between different stakeholders is lacking but it is desired for the inclusive implementation of AVs.
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| 26. |
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| 27. |
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| 28. |
- Uhlén, Mathias, et al.
(författare)
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A human protein atlas for normal and cancer tissues based on antibody proteomics
- 2005
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Ingår i: Molecular & Cellular Proteomics. - 1535-9476 .- 1535-9484. ; 4:12, s. 1920-1932
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Tidskriftsartikel (refereegranskat)abstract
- Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database containing, in the first version, similar to 400,000 high resolution images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this analysis to the majority of all human proteins thus providing a valuable tool for medical and biological research.
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