| 1. |
- Csajbok, Ludvig Z, 1964, et al.
(författare)
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Apolipoprotein E polymorphism in aneurysmal subarachnoid haemorrhage in West Sweden.
- 2016
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Ingår i: Acta neurologica Scandinavica. - : Hindawi Limited. - 1600-0404 .- 0001-6314. ; 133:6, s. 466-474
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Tidskriftsartikel (refereegranskat)abstract
- Aneurysmal subarachnoid haemorrhage (aSAH) is associated with high morbidity and mortality despite novel treatments. Genetic variability may explain outcome differences. Apolipoprotein E (ApoE) is a glycoprotein with a major role in brain lipoprotein metabolism. It has three isoforms encoded by distinct alleles: APOEε2, APOEε3 and APOEε4. The APOEε4 allele is associated with Alzheimer's disease and worse outcome after traumatic brain injury and ischaemic stroke. This prospective blinded study explored the influence of the APOEε4 polymorphism on the risk of aSAH, risk of cerebral vasospasm (CVS) and 1-year neurological outcome.
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| 2. |
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| 3. |
- Ali, Muhammad, et al.
(författare)
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Leveraging large multi-center cohorts of Alzheimer disease endophenotypes to understand the role of Klotho heterozygosity on disease risk.
- 2022
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 17:5
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Tidskriftsartikel (refereegranskat)abstract
- Two genetic variants in strong linkage disequilibrium (rs9536314 and rs9527025) in the Klotho (KL) gene, encoding a transmembrane protein, implicated in longevity and associated with brain resilience during normal aging, were recently shown to be associated with Alzheimer disease (AD) risk in cognitively normal participants who are APOE ε4 carriers. Specifically, the participants heterozygous for this variant (KL-SVHET+) showed lower risk of developing AD. Furthermore, a neuroprotective effect of KL-VSHET+ has been suggested against amyloid burden for cognitively normal participants, potentially mediated via the regulation of redox pathways. However, inconsistent associations and a smaller sample size of existing studies pose significant hurdles in drawing definitive conclusions. Here, we performed a well-powered association analysis between KL-VSHET+ and five different AD endophenotypes; brain amyloidosis measured by positron emission tomography (PET) scans (n = 5,541) or cerebrospinal fluid Aβ42 levels (CSF; n = 5,093), as well as biomarkers associated with tau pathology: the CSF Tau (n = 5,127), phosphorylated Tau (pTau181; n = 4,778) and inflammation: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2; n = 2,123) levels. Our results found nominally significant associations of KL-VSHET+ status with biomarkers for brain amyloidosis (e.g., CSF Aβ positivity; odds ratio [OR] = 0.67 [95% CI, 0.55-0.78], β = 0.72, p = 0.007) and tau pathology (e.g., biomarker positivity for CSF Tau; OR = 0.39 [95% CI, 0.19-0.77], β = -0.94, p = 0.007, and pTau; OR = 0.50 [95% CI, 0.27-0.96], β = -0.68, p = 0.04) in cognitively normal participants, 60-80 years old, who are APOE e4-carriers. Our work supports previous findings, suggesting that the KL-VSHET+ on an APOE ε4 genotype background may modulate Aβ and tau pathology, thereby lowering the intensity of neurodegeneration and incidence of cognitive decline in older controls susceptible to AD.
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| 4. |
- Deming, Y., et al.
(författare)
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The MS4A gene cluster is a key modulator of soluble TREM2 and Alzheimer's disease risk
- 2019
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Ingår i: Science Translational Medicine. - : American Association for the Advancement of Science (AAAS). - 1946-6234 .- 1946-6242. ; 11:505
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Tidskriftsartikel (refereegranskat)abstract
- Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in cerebrospinal fluid (CSF) has been associated with Alzheimer's disease (AD). TREM2 plays a critical role in microglial activation, survival, and phagocytosis; however, the pathophysiological role of sTREM2 in AD is not well understood. Understanding the role of sTREM2 in AD may reveal new pathological mechanisms and lead to the identification of therapeutic targets. We performed a genome-wide association study (GWAS) to identify genetic modifiers of CSF sTREM2 obtained from the Alzheimer's Disease Neuroimaging Initiative. Common variants in the membrane-spanning 4-domains subfamily A (MS4A) gene region were associated with CSF sTREM2 concentrations (rs1582763; P = 1.15 x 10(-15)); this was replicated in independent datasets. The variants associated with increased CSF sTREM2 concentrations were associated with reduced AD risk and delayed age at onset of disease. The single-nucleotide polymorphism rs1582763 modified expression of the MS4A4A and MS4A6A genes in multiple tissues, suggesting that one or both of these genes are important for modulating sTREM2 production. Using human macrophages as a proxy for microglia, we found that MS4A4A and TREM2 colocalized on lipid rafts at the plasma membrane, that sTREM2 increased with MS4A4A overexpression, and that silencing of MS4A4A reduced sTREM2 production. These genetic, molecular, and cellular findings suggest that MS4A4A modulates sTREM2. These findings also provide a mechanistic explanation for the original GWAS signal in the MS4A locus for AD risk and indicate that TREM2 may be involved in AD pathogenesis not only in TREM2 risk-variant carriers but also in those with sporadic disease.
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| 5. |
- Jönsson, Anders, 1959, et al.
(författare)
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Local anesthetics improve dermal perfusion after burn injury.
- 1998
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Ingår i: The Journal of burn care & rehabilitation. - 0273-8481. ; 19:1 Pt 1, s. 50-6
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Tidskriftsartikel (refereegranskat)abstract
- Deep partial-thickness burn injury was induced in the abdominal skin of anesthetized rats. Dermal perfusion was assessed by laser Doppler flowmetry. In the first set of experiments, one group of rats (n = 15) was topically treated with a lidocaine-prilocaine cream 5% (25 mg of each in 1 g) for 6 hours, starting 5 minutes after inducing the burn injury. In one control group (n = 14), the thermal injury was treated with placebo cream. Results showed a markedly reduced perfusion in the skin of the control animals within the first hour after burn injury, with further decrease during the following 5 hours of observation. In animals treated with the lidocaine-prilocaine cream, skin perfusion in the burned area was significantly increased during the first 30 minutes after the burn injury compared to before the burn (p < 0.01), followed by a decrease to a level below the preburn stage but significantly higher than that of control animals during the first hour after burn injury (p < 0.05). As opposed to burned control animals, skin perfusion gradually recovered toward preburn levels at the end of the experiment in local anesthetic-treated animals. In the second experimental set, four groups of animals were burned and subsequently treated with a bolus dose of lidocaine intravenously (2 mg/kg), followed by continuous intravenous lidocaine infusions at a rate of 50 (n = 10), 100 (n = 11), or 150 (n = 10) micrograms.kg-1.min-1. The infusions were started 5 minutes after the burn injury and lasted for 6 hours. Corresponding volumes of saline solution were given to burned control animals (n = 10). Results showed a significantly improved skin perfusion in the lidocaine-treated group in a dose-response fashion as compared to control animals. A maximum improvement of dermal perfusion in the burned area was induced by intravenous lidocaine at an infusion rate of 150 micrograms.kg-1.min-1 as compared to burned controls treated with isotonic saline solution infusions (p < 0.01). Results showed that topical or systemic administration of local anesthetics can prevent progressive dermal ischemia after thermal injury.
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| 6. |
- Jönsson, Anders, 1959, et al.
(författare)
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Topical local anaesthetics (EMLA) inhibit burn-induced plasma extravasation as measured by digital image colour analysis.
- 1998
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Ingår i: Burns : journal of the International Society for Burn Injuries. - 0305-4179. ; 24:4, s. 313-8
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Tidskriftsartikel (refereegranskat)abstract
- Amide local anaesthetics have previously been shown to reduce oedema and improve dermal perfusion following experimental burns. Previous studies have used invasive techniques for burn oedema quantification which do not allow continuous monitoring in the same animal. The present study used digital image colour analysis to investigate the effect of topical local anaesthetics on burn-induced extravasation of Evans blue albumin. A standardised full-thickness burn injury (1 x 1 cm) was induced in the abdominal skin of anaesthetised rats. The burn area was subsequently covered with 0.5 g of lidocaine-prilocaine cream 5% (25 mg of each in 1 g; EMLA, ASTRA, Sweden) or placebo cream during the first hour post-burn. One hour after the burn trauma, animals received Evans blue dye intravenously. Skin colour appearances were recorded by macrophotography before the burn and 5, 60. 65, 90, 120, 150, and 180 min post-burn. Colour slides were digitised and colour changes were analysed using the normalised red-green-blue (n-rgb) colour system. Results showed a significant inhibition of Evans blue extravasation between 60 and 180 min post-burn in EMLA-treated animals versus controls. Topical local anaesthetics are potent inhibitors of burn-induced plasma albumin extravasation, probably by direct action on vascular permeability and by inhibition of various steps of the pathophysiological response after burn injury.
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| 7. |
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| 8. |
- Nellgård, Per, 1956, et al.
(författare)
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Small-bowel obstruction and the effects of lidocaine, atropine and hexamethonium on inflammation and fluid losses.
- 1996
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Ingår i: Acta anaesthesiologica Scandinavica. - 0001-5172. ; 40:3, s. 287-92
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Tidskriftsartikel (refereegranskat)abstract
- The profuse fluid losses and morbidity of patients suffering from obstructive ileus are closely related to inflammatory changes in the obstructed bowel wall. Previous experimental studies have shown that use of steroids and NSAIDs can reduce fluid losses in obstructive ileus. In the present study, we investigated the effects of lidocaine on fluid losses since local anesthetics have been shown to possess wide and potent anti-inflammatory properties. Hexamethonium and atropine were used to study the importance of the autonomic nervous system in bowel obstruction.
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| 9. |
- Olofsson, Christina, et al.
(författare)
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A multicenter clinical study of the safety and activity of maleimide-polyethylene glycol-modified Hemoglobin (Hemospan) in patients undergoing major orthopedic surgery.
- 2006
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Ingår i: Anesthesiology. - : Ovid Technologies (Wolters Kluwer Health). - 0003-3022 .- 1528-1175. ; 105:6, s. 1153-63
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Hemospan (Sangart Inc., San Diego, CA), a polyethylene glycol-modified hemoglobin with unique oxygen transport properties, has successfully completed a phase I trial in healthy volunteers. Because adverse events are expected to increase with age, the authors conducted a phase II safety study of Hemospan in elderly patients undergoing elective hip arthroplasty during spinal anesthesia. METHODS: Ninety male and female patients, American Society of Anesthesiologists physical status I-III, aged 50-89 yr, in six Swedish academic hospitals were randomly assigned to receive either 250 or 500 ml Hemospan or Ringer's acetate (30 patients/group) before induction of spinal anesthesia. Safety assessment included vital signs and Holter monitoring from infusion to 24 h, evaluation of laboratory values, and fluid balance. The hypothesis to be tested was that the incidence of adverse events would be no more frequent in patients who received Hemospan compared with standard of care (Ringer's acetate). RESULTS: Three serious adverse events were noted, none of which was deemed related to study treatment. Liver enzymes, amylase, and lipase increased transiently in patients in all three groups. There were no significant differences in electrocardiogram or Holter parameters, but there was a suggestion of more bradycardic events in the treated groups. Hypotension was less frequent in the treated patients compared with controls. CONCLUSIONS: In comparison with Ringer's acetate, Hemospan mildly elevates hepatic enzymes and lipase and is associated with less hypotension and more bradycardic events. The absence of a high frequency of serious adverse events suggests that further clinical trials should be undertaken.
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| 10. |
- Remnestål, Julia, et al.
(författare)
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CSF profiling of the human brain enriched proteome reveals associations of neuromodulin and neurogranin to Alzheimer's disease
- 2016
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Ingår i: PROTEOMICS - Clinical Applications. - : Wiley-VCH Verlagsgesellschaft. - 1862-8346 .- 1862-8354. ; 10:12, s. 1242-1253
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study is part of a larger effort aiming to expand the knowledge of brain-enriched proteins in human cerebrospinal fluid (CSF) and to provide novel insight into the relation between such proteins and different neurodegenerative diseases. Experimental design: Here 280 brain-enriched proteins in CSF from patients with Alzheimer's disease (AD), Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are profiled. In total, 441 human samples of ventricular CSF collected post mortem and lumbar CSF collected ante mortem are analyzed using 376 antibodies in a suspension bead array setup, utilizing a direct labelling approach. Results: Among several proteins displaying differentiated profiles between sample groups, we focus here on two synaptic proteins, neuromodulin (GAP43) and neurogranin (NRGN). They are both found at elevated levels in CSF from AD patients in two independent cohorts, providing disease-associated profiles in addition to verifying and strengthening previously observed patterns. Increased levels are also observed for patients for whom the AD diagnosis was not established at the time of sampling. Conclusions and clinical relevance: These findings indicate that analyzing the brain-enriched proteins in CSF is of particular interest to increase the understanding of the CSF proteome and its relation to neurodegenerative disorders. In addition, this study lends support to the notion that measurements of these synaptic proteins could potentially be of great relevance in future diagnostic tests for AD.
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| 11. |
- Tarnow, Peter, 1963, et al.
(författare)
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Effects of D-myo-Inositol-1,2,6-triphosphate on eicosanoid formation in burned skin.
- 1996
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Ingår i: The Journal of surgical research. - 0022-4804. ; 62:1, s. 1-4
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Tidskriftsartikel (refereegranskat)abstract
- D-myo-Inositol-1,2,6-triphosphate (IP3) has been shown to reduce edema and progressive ischemia following experimental skin burns. The mechanism(s) are not identified but could be related to antiinflammatory effects of the agent. In the present ex vivo study we compared the effects of IP3 with those of saline and indomethacin on eicosanoid formation by normal and burned rat skin. In burned skin IP 3 treatment reduced the release of thromboxane B2 (TXB2) (P < 0.01) and leukotriene B4 (LTB 4) (P < 0.05) but there was only a weak trend for less prostaglandin E (PGE) compared to burned control animals receiving saline. Indomethacin reduced the release of TXB2 (P < 0.01), and PGE (P < 0.001), but not LTB 4 from burned skin compared to skin from saline-treated burned animals. In non-burned skin IP 3 increased the release of PGE (P < 0.01) and LTB 4 (P < 0.01), but did not significantly influence TXB2 accumulation in the incubation fluid compared to the saline-treated group. Indomethacin reduced the release of TXB2 (P < 0.001) and PGE (P < 0.001), but increased LTB 4 (P < 0.001) in normal skin compared to the saline-treated group. In conclusion, IP 3 inhibited the release of TXB2 and LTB 4 from burned skin ex vivo, but increased PGE and LTB 4 release from normal skin. These results suggest that the mode of action of IP 3 differs from that of nonsteroidal antiinflammatory drugs. The effects of IP 3 on the arachidonic acid cascade also seem to differ in burned versus normal skin.
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| 12. |
- Tarnow, Peter, 1963, et al.
(författare)
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Reduced albumin extravasation in experimental rat skin and muscle burn injury by D-myo-inositol-1,2,6-trisphosphate treatment.
- 1996
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Ingår i: The Journal of burn care & rehabilitation. - 0273-8481. ; 17:3, s. 207-12
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Tidskriftsartikel (refereegranskat)abstract
- This study investigated the effects of the anti-inflammatory agent D-myo-inositol-1,2,6-trisphosphate (IP3) on burn edema. Two sets of experiments were performed. In the first set, a full-thickness burn injury was induced in the abdominal skin of anesthetized rats. Postburn intravenous treatment was given with IP3, indomethacin or saline solution. Extravasation of Evans blue albumin in the burned tissue was quantified by a spectrophotometric technique. Results showed significant inhibition of albumin extravasation by IP3 in three of five different doses compared to saline-treated animals. In the second set of experiments, a deep full-thickness burn through the abdominal skin and rectus muscle was induced. The therapeutic window of IP3 could be more well-defined. Resulted showed a significant reduction of albumin extravasation in the skin at all four dose levels and in the abdominal muscle at three of four doses. Indomethacin had no significant effect on postburn edema formation. The mechanisms responsible for the inhibition of albumin leakage by IP3 could be secondary to reduced formation of edema-promoting inflammatory mediators by the agent, resulting in improved vascular patency.
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