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Sökning: WFRF:(Almqvist Erik G)

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1.
  • Flentie, Kelly, et al. (författare)
  • Chemical disarming of isoniazid resistance in Mycobacterium tuberculosis
  • 2019
  • Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : The National Academy of Scionces of the United States of America. - 0027-8424 .- 1091-6490. ; 116:21, s. 10510-10517
  • Tidskriftsartikel (refereegranskat)abstract
    • Mycobacterium tuberculosis (Mtb) killed more people in 2017 than any other single infectious agent. This dangerous pathogen is able to withstand stresses imposed by the immune system and tolerate exposure to antibiotics, resulting in persistent infection. The global tuberculosis (TB) epidemic has been exacerbated by the emergence of mutant strains of Mtb that are resistant to frontline antibiotics. Thus, both phenotypic drug tolerance and genetic drug resistance are major obstacles to successful TB therapy. Using a chemical approach to identify compounds that block stress and drug tolerance, as opposed to traditional screens for compounds that kill Mtb, we identified a small molecule, C10, that blocks tolerance to oxidative stress, acid stress, and the frontline antibiotic isoniazid (INH). In addition, we found that C10 prevents the selection for INH-resistant mutants and restores INH sensitivity in otherwise INH-resistant Mtb strains harboring mutations in the katG gene, which encodes the enzyme that converts the prodrug INH to its active form. Through mechanistic studies, we discovered that C10 inhibits Mtb respiration, revealing a link between respiration homeostasis and INH sensitivity. Therefore, by using C10 to dissect Mtb persistence, we discovered that INH resistance is not absolute and can be reversed.
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2.
  • Almqvist, Erik G., et al. (författare)
  • Factors influencing insulin sensitivity in patients with mild primary hyperparathyroidism before and after parathyroidectomy
  • 2012
  • Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 72:2, s. 92-99
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. Primary hyperparathyroidism (PHPT) is associated with cardiovascular disease. The aims of this study were to investigate lipid and glucose metabolism in mild PHPT, and to identify whether insulin sensitivity correlates with circulating levels of adiponectin, SHBG, and osteocalcin before and after parathyroidectomy (PTX). Materials and methods. Forty-five patients with PHPT were examined before and 1 year after PTX. Circulating levels of triglycerides, total cholesterol, HDL-cholesterol, insulin, glucose, adiponectin, SHBG, osteocalcin, and erythropoietin were measured. Results. At baseline, the mean serum levels of total cholesterol, LDL-cholesterol and triglycerides were above the upper reference limit or in the upper normal range, and insulin sensitivity was reduced as assessed using the HOMA index. One year after parathyroidectomy, serum lipids as well as HOMA index and erythropoietin were unchanged while adiponectin had increased (p < 0.05), and SHBG and osteocalcin had decreased (p < 0.05 and p < 0.0001, respectively). HOMA index correlated negatively with circulating levels of adiponectin, SHBG and osteocalcin. In multiple regression analysis SHBG was the most important predictor of insulin sensitivity, both pre- and postoperatively. Conclusion. Untreated mild PHPT is associated with a moderate derangement of lipid and glucose metabolism. As previously shown in population-based cohorts, insulin sensitivity is positively associated with circulating concentrations of adiponectin, SHBG and osteocalcin. One year after PTX, the mean level of adiponectin was increased, but the levels of SHBG and osteocalcin had decreased and the levels of serum lipids and the insulin sensitivity remained unchanged as compared with baseline.
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3.
  • Almqvist, Erik G., et al. (författare)
  • Increased markers of inflammation and endothelial dysfunction in patients with mild primary hyperparathyroidism
  • 2011
  • Ingår i: Scandinavian Journal of Clinical & Laboratory Investigation. - : Informa UK Limited. - 1502-7686 .- 0036-5513. ; 71:2, s. 139-144
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives: The association between primary hyperparathyroidism (PHPT) and cardiovascular disease is incompletely understood. The aims of this study were to evaluate how cardiac function and markers of inflammation and endothelial dysfunction correlate in patients with mild PHPT, and how these markers are influenced by surgical cure of the parathyroid disease (PTX). Material and methods: Forty-five patients with PHPT were examined before and 1 year after PTX. Serum/plasma concentrations of calcium, PTH, highly sensitive C-reactive protein (CRP), interleukin-6 (IL-6), vascular adhesion molecule-1 (VCAM1), E-selectin, and NT-proBNP were measured as well as erythrocyte sedimentation rate (ESR) and creatinine clearance. Cardiac function was evaluated by equilibrium radionuclide angiography. Results: The baseline serum level of IL-6 correlated negatively with baseline parameters of cardiac function (exercise capacity, p < 0.001, left ventricular ejection fraction at exercise, p < 0.01). The mean serum concentrations of IL-6 and CRP and the ESR had increased 1 year after PTX (p < 0.001, p < 0.01, and p < 0.001, respectively) in parallel with a decrease in cardiac function and an increase in circulating NT-proBNP. The mean serum level of VCAM1 was above the upper normal range at baseline and had not changed significantly 1 year after PTX. Conclusion: Patients with mild PHPT and normal renal function displayed signs of subclinical inflammation and endothelial dysfunction. One year after PTX, the inflammatory markers were increased in parallel with a subclinical decrease in cardiac function. Further studies are warranted to clarify the natural course and clinical implications of these changes.
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4.
  • Andersson, Emma K., et al. (författare)
  • Modulation of Curli Assembly and Pellicle Biofilm Formation by Chemical and Protein Chaperones
  • 2013
  • Ingår i: Chemistry and Biology. - : Elsevier. - 1074-5521 .- 1879-1301. ; 20:10, s. 1245-1254
  • Tidskriftsartikel (refereegranskat)abstract
    • Enteric bacteria assemble functional amyloid fibers, curli, on their surfaces that share structural and biochemical properties with disease-associated amyloids. Here, we test rationally designed 2-pyridone compounds for their ability to alter amyloid formation of the major curli subunit CsgA. We identified several compounds that discourage CsgA amyloid formation and several compounds that accelerate CsgA amyloid formation. The ability of inhibitor compounds to stop growing CsgA fibers was compared to the same property of the CsgA chaperone, CsgE. CsgE blocked CsgA amyloid assembly and arrested polymerization when added to actively polymerizing fibers. Additionally, CsgE and the 2-pyridone inhibitors prevented biofilm formation by Escherichia coli at the air-liquid interface of a static culture. We demonstrate that curli amyloid assembly and curli-dependent biofilm formation can be modulated not only by protein chaperones, but also by "chemical chaperones."
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5.
  • Dalemo, Sofia, et al. (författare)
  • Long-term follow-up of patients with elevated serum calcium concentration in Swedish primary care
  • 2013
  • Ingår i: Scandinavian Journal of Primary Health Care. - : Informa UK Limited. - 0281-3432 .- 1502-7724. ; 31:4, s. 248-254
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective. To follow up patients with elevated calcium concentrations after 10 years. Design. Longitudinal, using medical records, questionnaires, and clinical investigation. Setting. Primary care in Tibro, Sweden, 2008–2010. Subjects. 127 patents with elevated calcium concentrations and 254 patients with normal calcium concentrations from the local community, attending the health care centre. Main outcome measures. Diagnoses and mortality in patients with elevated calcium concentrations in 1995–2000, compared with patients with normal calcium concentrations and the background population. Results. The proportion of patients for whom no underlying cause was detected decreased from 55% at baseline to 12% at follow-up. Primary hyperparathyroidism was most common in women, 23% at baseline and 36% at follow-up, and the cancer prevalence increased from 5% to 12% in patients with elevated calcium concentration. Mortality tended to be higher in men with elevated calcium concentrations compared with men with normal calcium concentrations, and was significantly higher than in the background population (SMR 2.3, 95% CI 1.3–3.8). Cancer mortality was significantly increased in men (p = 0.039). Low calcium concentrations were also associated with higher mortality (p = 0.004), compared with patients with normal calcium concentrations. Conclusion. This study underscores the importance of investigating patients with increased calcium concentrations suggesting that most of these patients – 88% in our study – will turn out to have an underlying disease associated with hypercalcaemia during a 10-year follow-up period. Elevated calcium concentrations had a different disease pattern in men and women, with men showing increased cancer mortality in this study. Read More: http://informahealthcare.com/doi/abs/10.3109/02813432.2013.861152
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7.
  • Johansson, Per, 1966, et al. (författare)
  • Cerebrospinal fluid substance P concentrations are elevated in patients with Alzheimer's disease.
  • 2015
  • Ingår i: Neuroscience letters. - : Elsevier BV. - 1872-7972 .- 0304-3940. ; 609, s. 58-62
  • Tidskriftsartikel (refereegranskat)abstract
    • The neuropeptides substance P, orexin A (hypocretin-1) and neurotensin are signaling molecules that influence brain activity. We examined their cerebrospinal fluid (CSF) levels in a study population consisting of Alzheimer's disease (AD) dementia or mild cognitive impairment (MCI) diagnosed with AD dementia upon follow-up (n=32), stable MCI (SMCI, n=13), other dementias (n=15), and healthy controls (n=20). CSF substance P level was increased in AD patients compared to patients with other dementias and healthy controls (P<0.05 and P<0.01, respectively). Patients with other dementia or SMCI had lower CSF orexin A level than AD patients (both P<0.05) and marginally lower level than healthy controls (both P=0.05). CSF neurotensin level was similar in all groups. In the total study population (n=80), CSF substance P level correlated positively with CSF levels of T-tau and P-tau, and in AD patients (n=32), CSF substance P level correlated positively with CSF Aβ1-42 level. In conclusion, CSF substance P level was elevated in AD patients and correlated with CSF Aβ1-42 level, a well established marker of senile plaque pathology. The role of low CSF orexin A level in other dementias or SMCI needs to be explored in further studies.
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8.
  • Johansson, Per, 1966, et al. (författare)
  • Reduced Cerebrospinal Fluid Concentration of Apolipoprotein A-I in Patients with Alzheimer's Disease.
  • 2017
  • Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908 .- 1387-2877. ; 59:3, s. 1017-1026
  • Tidskriftsartikel (refereegranskat)abstract
    • Apolipoprotein E (ApoE) has been extensively studied in Alzheimer's disease (AD), but little is known of apolipoprotein A-I (ApoA-I) in cerebrospinal fluid (CSF).Plasma lipids as well as ApoA-I and ApoE in plasma and CSF were determined and related to Mini-Mental State Examination (MMSE) score, APOE genotype, and CSF AD biomarkers.Consecutive patients with AD (n=29), stable mild cognitive impairment (n=13), other dementias (n=14), and healthy controls (n=18) were included at a single center.AD patients had higher plasma triglycerides and lower CSF ApoA-I concentration than controls (both p<0.05). CSF ApoE concentration was reduced in other dementias (p<0.01). In AD as well as other dementias, the ratios between CSF and plasma concentrations of both ApoA-I and ApoE were lower than those in the controls. ApoA-I and ApoE in plasma and CSF were not influenced by APOEɛ4 allele distribution. In the total study population (n=74), CSF ApoA-I correlated positively with MMSE score (r=0.26, p<0.05) and negatively with CSF P-tau (r=-0.25, p<0.05). CSF ApoE correlated positively with CSF concentrations of T-tau and P-tau in the total study population and in AD patients.CSF ApoA-I was reduced in AD patients and associated with measures of cognitive function and AD disease status. The mechanisms underlying the decreased CSF:plasma ratios of ApoA-I and ApoE in AD and other dementias need to be explored in further studies.
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9.
  • Johansson, Per, 1966, et al. (författare)
  • Reduced cerebrospinal fluid concentration of interleukin-12/23 subunit p40 in patients with cognitive impairment.
  • 2017
  • Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 12:5
  • Tidskriftsartikel (refereegranskat)abstract
    • The role of inflammation in Alzheimer's disease (AD) and other cognitive disorders is unclear. In a well-defined mono-center population, we measured cytokines and chemokines in paired serum and cerebrospinal fluid (CSF) samples.Consecutive patients with AD (n = 30), stable mild cognitive impairment (SMCI, n = 11), other dementias (n = 11), and healthy controls (n = 18) were included. None of the subjects was treated with glucocorticoids, cholinesterase inhibitors, or non-steroidal anti-inflammatory drugs. Serum and CSF concentrations of interleukin-6 (IL-6), IL-8, IL-12/23 p40, IL-15, IL-16, vascular endothelial growth factor-A (VEGF-A), and three chemokines were measured using a multiplex panel.After correction for multiple comparisons, only CSF IL-12/23 p40 concentration differed significantly between the total patient group (n = 52) and controls (n = 18; p = 0.002). Further analyses showed that CSF IL-12/23 p40 concentration was decreased in all patient subgroups (AD, other dementias, and SMCI) compared to healthy controls (p < 0.01, p < 0.05, and p < 0.05, respectively). In the total study population (n = 70), CSF IL-12/23 p40 concentrations correlated positively with CSF concentrations of β-amyloid1-42 (Aβ1-42) and phosphorylated tau protein (P-tau) whereas in AD patients (n = 30), CSF IL-12/23 p40 only correlated positively with CSF P-Tau (r = 0.46, p = 0.01).Most cytokines and chemokines were similar in patients and controls, but CSF IL-12/23 subunit p40 concentration was decreased in patients with cognitive impairment, and correlated with markers of AD disease status. Further studies are needed to evaluate the role of CSF IL-12/23 p40 in other dementias and SMCI.
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10.
  • Johansson, Per, et al. (författare)
  • Reduced cerebrospinal fluid level of thyroxine in patients with Alzheimer's disease
  • 2013
  • Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 38:7, s. 1058-1066
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Little is known of the association between thyroid hormones in the central nervous system and Alzheimer's disease (AD). We determined thyroid hormone levels in serum and cerebrospinal fluid (CSF) in a well-defined homogeneous mono-center population. Methods: Fifty-nine consecutive patients under primary evaluation for cognitive impairment were recruited. The participants included patients with AD or mild cognitive impairment (MCI) diagnosed with AD upon follow-up (n = 31), patients with stable MCI (SMCI, n = 13), patients with other dementias (n = 15), and healthy controls (n = 19). Thyroid hormones in serum and CSF and AD biomarkers in CSF were analyzed using established immunochemical assays. Cognitive impairment was estimated using mini-mental state examination (MMSE). Results: Serum levels of free and total thyroxine (T4) and triiodothyronine (T3) were similar in all groups whereas a marginal increase in serum thyroid-stimulating hormone (TSH) level was observed in the AD patients. The CSF level of total T4 was decreased in patients with AD and other dementias compared to SMCI (both P = 0.01) and healthy controls (both P = 0.001), whereas CSF levels of TSH and total T3 were unchanged. In the total study population, CSF total 14 level correlated positively with MMSE score (r = 0.26, P < 0.05) and negatively with CSF total-tau (T-Tau) level (r = -0.23, P < 0.05). Conclusion: Patients with AD as well as other dementias had signs of mild brain hypothyroidism, which could only to a small extent be detected in serum values. (C) 2012 Elsevier Ltd. All rights reserved.
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