| 1. |
- Lundmark, Katarzyna, et al.
(författare)
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Transmissibility of systemic amyloidosis by a prion-like mechanism
- 2002
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 99:10, s. 6979-6984
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Tidskriftsartikel (refereegranskat)abstract
- The generation of amyloid fibrils from an amyloidogenic polypeptide occurs by a nucleation-dependent process initiated in vitro by seeding the protein solution with preformed fibrils. This phenomenon is evidenced in vivo by the fact that amyloid protein A (AA) amyloidosis in mice is markedly accelerated when the animals are given, in addition to an inflammatory stimulus, an i.v. injection of protein extracted from AA amyloid-laden mouse tissue. Heretofore, the chemical nature of this “amyloid enhancing factor” (AEF) has not been definitively identified. Here we report that the active principle of AEF extracted from the spleen of mice with silver nitrate-induced AA amyloidosis was identified unequivocally as the AA fibril itself. Further, we demonstrated that this material was extremely potent, being active in doses <1 ng, and that it retained its biologic activity over a considerable length of time. Notably, the AEF was also effective when administered orally. Our studies have provided evidence that AA and perhaps other forms of amyloidosis are transmissible diseases, akin to the prion-associated disorders.
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| 2. |
- Canetti, Diana, et al.
(författare)
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Clinical ApoA-IV amyloid is associated with fibrillogenic signal sequence
- 2021
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Ingår i: Journal of Pathology. - : John Wiley & Sons. - 0022-3417 .- 1096-9896. ; 255:3, s. 311-318
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein A-IV amyloidosis is an uncommon form of the disease normally resulting in renal and cardiac dysfunction. ApoA-IV amyloidosis was identified in 16 patients attending the National Amyloidosis Centre and in eight clinical samples received for histology review. Unexpectedly, proteomics identified the presence of ApoA-IV signal sequence residues (p.18-43 to p.20-43) in 16/24 trypsin-digested amyloid deposits but in only 1/266 non-ApoA-IV amyloid samples examined. These additional signal residues were also detected in the cardiac sample from the Swedish patient in which ApoA-IV amyloid was first described, and in plasma from a single cardiac ApoA-IV amyloidosis patient. The most common signal-containing peptide observed in ApoA-IV amyloid, p.20-43, and to a far lesser extent the N-terminal peptide, p.21-43, were fibrillogenic in vitro at physiological pH, generating Congo red-positive fibrils. The addition of a single signal-derived alanine residue to the N-terminus has resulted in markedly increased fibrillogenesis. If this effect translates to the mature circulating protein in vivo, then the presence of signal may result in preferential deposition as amyloid, perhaps acting as seed for the main circulating native form of the protein; it may also influence other ApoA-IV-associated pathologies. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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| 3. |
- Maggino, L., et al.
(författare)
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Cystic Pancreatic Neuroendocrine Neoplasms : A Multicenter International Cohort Study
- 2019
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Ingår i: Neuroendocrinology. - : S. Karger. - 0028-3835 .- 1423-0194. ; 108:Suppl. 1, s. 245-245
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Natural history of cystic pancreatic neuroendocrine neoplasms (cPanNENs) is unknown, and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series.Aim(s): Analyze a large international cohort of cPanNENs.Materials and methods: All resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors and MEN-1 patients were excluded. Malignancy was defined as G3 grading, lymph node (LN) involvement, metastasis and/or recurrence.Results: Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were preoperatively >2cm. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound (EUS, OR 3.01, 95%CI 1.66-5.44) and nuclear medicine investigations (OR 3.97, 95%CI 1.93-8.18), and for those managed in high-volume institutions (OR 3.48, 95%CI 1.88-6.45). Forty-one cPanNENs (15.6%) were malignant. Suspicion of LN involvement on imaging, age >65 years, preoperative size >2cm and pancreatic duct dilation were independently associated with malignancy in the whole cohort. In asymptomatic patients, older age and a preoperative size >2cm remained independently associated with malignancy. Notably, malignancy occurred in only 1/61 asymptomatic patients with a preoperative size ≤2cm.Conclusion: The diagnostic accuracy of cPanNENs is increased by the use of EUS and nuclear medicine investigations and is higher in high-volume institutions. A preoperative size >2cm is independently associated with malignancy, so that a wait-and-see policy for sporadic asymptomatic cPanNENs≤ 2cm seems justified.
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| 4. |
- Maggino, Laura, et al.
(författare)
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Reappraisal of a 2-Cm Cut-off Size for the Management of Cystic Pancreatic Neuroendocrine Neoplasms : A Multicenter International Study
- 2021
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Ingår i: Annals of Surgery. - : Wolters Kluwer. - 0003-4932 .- 1528-1140. ; 273:5, s. 973-981
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The aim of this study was to characterize an international cohort of resected cystic pancreatic neuroendocrine neoplasms (cPanNENs) and identify preoperative predictors of aggressive behavior.BACKGROUND: The characteristics of cPanNENs are unknown and their clinical management remains unclear. An observational strategy for asymptomatic cPanNENs ≤2 cm has been proposed by recent guidelines, but evidence is scarce and limited to single-institutional series.METHODS: Resected cPanNENs (1995-2017) from 16 institutions worldwide were included. Solid lesions (>50% solid component), functional tumors, and MEN-1 patients were excluded. Aggressiveness was defined as lymph node (LN) involvement, G3 grading, distant metastases, and/or recurrence.RESULTS: Overall, 263 resected cPanNENs were included, among which 177 (63.5%) were >2 cm preoperatively. A preoperative diagnosis of cPanNEN was established in 162 cases (61.6%) and was more frequent when patients underwent endoscopic ultrasound [EUS, odds ratio (OR) 2.69, 95% confidence interval (CI) 1.52-4.77] and somatostatin-receptor imaging (OR 3.681, 95% CI 1.809-7.490), and for those managed in specialized institutions (OR 3.12, 95% CI 1.57-6.21). Forty-one cPanNENs (15.6%) were considered aggressive. In the whole cohort, LN involvement on imaging, age >65 years, preoperative size >2 cm, and pancreatic duct dilation were independently associated with aggressive behavior. In asymptomatic patients, older age and a preoperative size >2 cm remained independently associated with aggressiveness. Only 1 of 61 asymptomatic cPanNENs ≤2 cm displayed an aggressive behavior.CONCLUSIONS: The diagnostic accuracy of cPanNENs is increased by the use of EUS and somatostatin-receptor imaging and is higher in specialized institutions. Preoperative size >2 cm is independently associated with aggressive behavior. Consequently, a watch-and-wait policy for sporadic asymptomatic cPanNENs ≤2 cm seems justified and safe for most patients.
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| 5. |
- Meijer, Laura L., et al.
(författare)
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Clinical characteristics and long-term outcomes following pancreatic injury – An international multicenter cohort study
- 2023
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Ingår i: Heliyon. - : CELL PRESS. - 2405-8440. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Trauma to the pancreas is rare but associated with significant morbidity. Currently available management guidelines are based on low-quality evidence and data on long-term outcomes is lacking. This study aimed to evaluate clinical characteristics and patient-reported long-term outcomes for pancreatic injury. Methods: A retrospective cohort study evaluating treatment for pancreatic injury in 11 centers across 5 European nations over >10 years was performed. Data relating to pancreatic injury and treatment were collected from hospital records. Patients reported quality of life (QoL), changes to employment and new or ongoing therapy due to index injury. Results: In all, 165 patients were included. The majority were male (70.9%), median age was 27 years (range: 6–93) and mechanism of injury predominantly blunt (87.9%). A quarter of cases were treated conservatively; higher injury severity score (ISS) and American Association for the Surgery of Trauma (AAST) pancreatic injury scores increased the likelihood for surgical, endoscopic and/or radiologic intervention. Isolated, blunt pancreatic injury was associated with younger age and pancreatic duct involvement; this cohort appeared to benefit from non-operative management. In the long term (median follow-up 93; range 8–214 months), exocrine and endocrine pancreatic insufficiency were reported by 9.3% of respondents. Long-term analgesic use also affected 9.3% of respondents, with many reported quality of life problems (QoL) potentially attributable to side-effects of opiate therapy. Overall, impaired QoL correlated with higher ISS scores, surgical therapy and opioid analgesia on discharge. Conclusions: Pancreatic trauma is rare but can lead to substantial short- and long-term morbidity. Near complete recovery of QoL indicators and pancreatic function can occur despite significant injury, especially in isolated, blunt pancreatic injury managed conservatively and when early weaning off opiate analgesia is achieved.
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| 6. |
- Nyström, Sofia N., et al.
(författare)
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AA-Amyloid is cleared by endogenous immunological mechanisms
- 2012
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Ingår i: Amyloid. - : Informa UK Limited. - 1350-6129 .- 1744-2818. ; 19:3, s. 138-145
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Tidskriftsartikel (refereegranskat)abstract
- Reactive amyloidosis is a complication to longstanding inflammatory diseases.Protein amyloid A (AA), an N-terminal fragment of the acute phase protein serumamyloid A, undergoes conformational changes and is deposited as amyloid in tissue.AA-amyloidosis is reversible and reduction of amyloid mass has been reported as theinflammation ceases. Not much is known about the endogenous factors thatcontribute to amyloid resolution. Herein, we describe the dynamics of amyloiddegradation in experimental murine AA-amyloidosis and show that amyloiddegradation depends on macrophages and antibody formation. AA-amyloidosis wasinduced in mice and resolution of amyloid was monitored over time by histologicaltechniques. Internalized amyloid was present in macrophages that appeared at siteof deposition. At 9 months, when virtually all amyloid was cleared, amyloidosis wasre-induced in one group of animals by a single silver nitrate injection. This causedeposition of excessive amounts of amyloid, and indicate that even thoughundetectable the amyloid reseed in the body and can there act as amyloid enhancingfactor. Antibodies directed against protein AA were detected in animals duringamyloid clearance by ELISA-technique. Passive immunization with an amyloidspecific monoclonal antibody, produced by a B-cell clone recovered from an animalwith advanced AA-amyloidosis, diminish amyloid deposits in murine AA-amyloidosis.Immunoglobulins co-localize with amyloid deposits and can contribute to amyloiddegradation by Fc-receptor mediated phagocytosis.
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| 7. |
- Nyström, Sofia N., et al.
(författare)
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Cardiac Amyloid in Experimental AA Amyloidosis is Associated with IncreasedAutophagic Activity
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Cardiac involvement in reactive amyloidosis is a severe complication that leads to reducedsurvival. We induced reactive amyloidosis in mice by induction of chronic inflammation andfound that cardiac involvement develops later than spleen and liver deposits. TEM studiesrevealed intracellular amyloid deposits, but endogenous production of SAA1, SAA2 or SAA3by the cardiomyocytes was not supported by mRNA analysis. Therefore, the intracellulardeposits of protein AA must derive from SAA produced at another location. Autophagosomeswere present in close association with intracellular amyloid and the autophagy marker LC3was increased 20 times in cardiac tissue with moderate amounts of amyloid. Increase in LC3was not paralleled by an increase in LAMP-2. The ER-stress marker Bip was unchanged ininflamed heart tissue and in amyloid-containing heart. Even though procaspase-12 increasedin heart after silver nitrate injections and in heart with AA-amyloid, no active caspase-12could be detected. We suggest that autophagosomes are involved in amyloid clearance, buttheir accumulation indicate that the formation of autophagolysosomes is hampered.
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| 8. |
- Nyström, Sofia N., 1974-
(författare)
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Deposition and Resolution of AA Amyloid
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Amyloidosis is a group of protein misfolding diseases characterized by extracellulardeposition of fibrillar protein aggregates. Today more than 25 different human amyloidogenicproteins have been identified, causing a variety of pathological conditions that includeAlzheimer’s disease, type 2 diabetes and prion diseases. Amyloid A (AA) amyloidosis is acomplication to long standing inflammatory disorders and amyloid is formed from N-terminalfragments of the acute phase protein serum amyloid A. AA amyloidosis developsspontaneously in many mice strains in response to inflammatory stimulation. Amyloidformation is nucleation dependent and develops after a lag phase of months. If an extract fromamyloid loaded tissue is administered to the animal, the lag phase is shortened to days. Thetissue extract is referred to as amyloid enhancing factor, AEF.In paper I we demonstrate that the active component of AEF is the amyloid fibril itself. We doalso show that AEF retains its activity over a long period of time and is active in very low(femtomolar) doses. AEF activity can be transmitted in a serial manner, also by oraladministration. Thus, AEF shares several characteristics with the infectious prion protein. Wetherefore suggest that AEF induces protein conformational changes in a prion like manner andthat experimental AA amyloidosis is a transmissible disease.In paper II we showed that peripheral blood monocytes recovered from mice with AAamyloidosis carry AEF activity but plasma does not. AA amyloid was detected in occasionalmonocytes. It is possible that these fibrils serve as seeds or nuclei for conformational changesand subsequent amyloid deposition in the recipient animal.In paper III mechanisms of amyloid clearance in experimental AA amyloidosis were studied.During amyloid clearance antibodies directed against AA were detected. Immunoglobulinsdid also co-localize with AA deposits. Amyloid fibrils were detected intracellular inmacrophages. These findings suggest that immune mechanisms contribute to AA amyloidclearance in mice and that macrophages are key players in the process. Immunoglobulins mayserve as opsonins facilitating phagocytosis of amyloid.It is believed that the early stages of amyloidogenesis are common in all forms of amyloiddiseases and that the amyloid formation process is cytotoxic. There are few studies onbiological effects of AA deposition in post mitotic tissue such as the heart. In paper IV weinvestigate the effects of cardiac AA amyloid deposition. Our results indicate that cardiac AAdeposition is associated with increased autophagic activity.In conclusion this thesis provides new insights to the dynamics of the turnover of AA amyloidand the mechanisms involved. Our results clearly show that the innate capacity of amyloidclearance is efficient.
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| 9. |
- Persson, Ann L, et al.
(författare)
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Validity of electrical stimulus magnitude matching in chronic pain
- 2009
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Ingår i: Journal of Rehabilitation Medicine. - 1650-1977 .- 1651-2081. ; 41:11, s. 898-903
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To examine the validity of the PainMatcher in chronic pain.Design: Comparison of parallel pain estimates from visual analogue scales with electrical stimulus magnitude matching.Patients: Thirty-one patients with chronic musculoskeletal pain.Methods: Twice a day ongoing pain was rated on a standard 100-mm visual analogue scale, and thereafter magnitude matching was performed using a PainMatcher. The sensory threshold to electrical stimulation was tested twice on separate occasions.Results: In 438 observations visual analogue scale ranged from 3 to 95 (median 41) mm, and PainMatcher magnitudes from 2.67 to 27.67 (median 6.67; mean 7.78) steps. There was little correlation between visual analogue scale and magnitude data (r = 0.29; p < 0.0001). The mean sensory threshold was 3.67 steps, indicating that the PainMatcher, on average, stimulated at 2.1 times the perception threshold at matching point.Conclusion: Electrical magnitude matching of chronic pain intensity elicited limited activation of nerve fibres at 2.0–2.2 times sensory threshold, indicating that the induced pain was evoked by coarse nociceptive Aδ fibres. While the visual analogue scale estimates covered the whole range of the instrument, the PainMatcher readings utilized only a small part of the instrument range and, importantly, had little or no relation to the visual analogue scale estimates. The validity of the PainMatcher procedure is doubtful.
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| 10. |
- Rutegård, Martin, et al.
(författare)
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Non-Steroidal Anti-Inflammatory Drug Use and Risk of Anastomotic Leakage after Anterior Resection : A Protocol-Based Study
- 2016
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Ingår i: Digestive Surgery. - : S. Karger AG. - 0253-4886 .- 1421-9883. ; 33:2, s. 129-135
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Tidskriftsartikel (refereegranskat)abstract
- Background: Non-steroidal anti-inflammatory drugs (NSAIDs) have been introduced as opioid-sparing analgesics in colorectal surgery. However, recent research has implicated these drugs as risk factors for anastomotic dehiscence.Methods: The Swedish Colorectal Cancer Registry was used to identify all patients operated with anterior resection for rectal cancer at centres that performed more than 25 abdominal operations per year, from 2007 to 2012, inclusive. The registry provided individual patient data on demographic variables and symptomatic anastomotic leakage. The patient exposure to NSAIDs was defined according to the protocol of the hospital at which the patient was operated. Logistic regression was employed to estimate ORs and 95% CIs, adjusting for confounders.Results: The study cohort comprised 2,605 patients operated at 21 centres. In the NSAID group, 102/1,458 (7.0%) suffered an anastomotic leak, as compared to 124/1,023 (10.8%) in the non-NSAID group. With adjustment for confounding, patients treated at NSAID hospitals had a reduced risk of developing anastomotic leakage (OR 0.68; 95% CI 0.48-0.96).Conclusions: In this retrospective protocol-based study, NSAIDs did not increase the risk of anastomotic leakage after anterior resection for rectal cancer. The postoperative use of NSAIDs may not be detrimental, but more research is warranted.
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