| 1. |
- Alaridah, Nader, et al.
(författare)
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Impaired CXCR1-dependent oxidative defence in active tuberculosis patients.
- 2015
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Ingår i: Tuberculosis. - : Elsevier BV. - 1873-281X .- 1472-9792. ; 95:6, s. 744-750
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Tidskriftsartikel (refereegranskat)abstract
- Much of the pronounced host inflammatory response that occurs in tuberculosis (TB) is related to failed immunity against the invading pathogen. The G-protein coupled receptors CXCR1 and CXCR2 are implicated in important signal transduction pathways in lung inflammatory responses. We investigated the expression and function of these receptors in a simple whole blood model from 24 patients with pulmonary TB and in subjects with latent TB infection (LTBI). Healthy controls were recruited from close contacts to the pulmonary index patients. We found that pulmonary TB patients had significantly increased CXCR1 expression on blood cells compared to LTBI subjects and controls (p < 0.001). In contrast, LTBI subjects had a significant increase in CXCR2 expression compared to pulmonary TB patients (p < 0.001) and controls (p < 0.01). Leukocyte function, measured as oxidative capacity, was decreased in pulmonary TB patients compared to LTBI and controls (p < 0.001) and correlated with the increased CXCR1 expression. Leukocyte recruitment, measured as the expression of microRNA-223 was increased in pulmonary TB patients compared to LTBI (p < 0.05). We found that variations in receptor expression are linked to disease progression and affect the immune response against Mycobacterium tuberculosis (Mtb).
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| 2. |
- Alaridah, Nader, et al.
(författare)
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Transmission dynamics study of tuberculosis isolates with whole genome sequencing in southern Sweden
- 2019
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Epidemiological contact tracing complemented with genotyping of clinical Mycobacterium tuberculosis isolates is important for understanding disease transmission. In Sweden, tuberculosis (TB) is mostly reported in migrant and homeless where epidemiologic contact tracing could pose a problem. This study compared epidemiologic linking with genotyping in a low burden country. Mycobacterium tuberculosis isolates (n = 93) collected at Scania University Hospital in Southern Sweden were analysed with the standard genotyping method mycobacterial interspersed repetitive units-variable number tandem repeats (MIRU-VNTR) and the results were compared with whole genome sequencing (WGS). Using a maximum of twelve single nucleotide polymorphisms (SNPs) as the upper threshold of genomic relatedness noted among hosts, we identified 18 clusters with WGS comprising 52 patients with overall pairwise genetic maximum distances ranging from zero to nine SNPs. MIRU-VNTR and WGS clustered the same isolates, although the distribution differed depending on MIRU-VNTR limitations. Both genotyping techniques identified clusters where epidemiologic linking was insufficient, although WGS had higher correlation with epidemiologic data. To summarize, WGS provided better resolution of transmission than MIRU-VNTR in a setting with low TB incidence. WGS predicted epidemiologic links better which could consolidate and correct the epidemiologically linked cases, avoiding thus false clustering.
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| 3. |
- Rao, Komal Umashankar, et al.
(författare)
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A broad spectrum anti-bacterial peptide with an adjunct potential for tuberculosis chemotherapy
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Alternative ways to prevent and treat infectious diseases are needed. Previously, we identified a fungal peptide, NZX, that was comparable to rifampicin in lowering M. tuberculosis load in a murine tuberculosis (TB) infection model. Here we assessed the potential synergy between this cationic host defence peptide (CHDP) and the current TB drugs and analysed its pharmacokinetics. We found additive effect of this peptide with isoniazid and ethambutol and confirmed these results with ethambutol in a murine TB-model. In vivo, the peptide remained stable in circulation and preserved lung structure better than ethambutol alone. Antibiotic resistance studies did not induce mutants with reduced susceptibility to the peptide. We further observed that this peptide was effective against nontuberculous mycobacteria (NTM), such as M. avium and M. abscessus, and several Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. In conclusion, the presented data supports a role for this CHDP in the treatment of drug resistant organisms.
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| 4. |
- Rao, Komal Umashankar, et al.
(författare)
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Mechanisms of a Mycobacterium tuberculosis Active Peptide
- 2023
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Ingår i: Pharmaceutics. - : MDPI AG. - 1999-4923. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Multidrug-resistant tuberculosis (MDR) continues to pose a threat to public health. Previously, we identified a cationic host defense peptide with activity against Mycobacterium tuberculosis in vivo and with a bactericidal effect against MDR M. tuberculosis at therapeutic concentrations. To understand the mechanisms of this peptide, we investigated its interactions with live M. tuberculosis and liposomes as a model. Peptide interactions with M. tuberculosis inner membranes induced tube-shaped membranous structures and massive vesicle formation, thus leading to bubbling cell death and ghost cell formation. Liposomal studies revealed that peptide insertion into inner membranes induced changes in the peptides’ secondary structure and that the membranes were pulled such that they aggregated without permeabilization, suggesting that the peptide has a strong inner membrane affinity. Finally, the peptide targeted essential proteins in M. tuberculosis, such as 60 kDa chaperonins and elongation factor Tu, that are involved in mycolic acid synthesis and protein folding, which had an impact on bacterial proliferation. The observed multifaceted targeting provides additional support for the therapeutic potential of this peptide.
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| 5. |
- Tenland, Erik, et al.
(författare)
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A novel derivative of the fungal antimicrobial peptide plectasin is active against Mycobacterium tuberculosis
- 2018
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Ingår i: Tuberculosis. - : Elsevier BV. - 1472-9792 .- 1873-281X. ; 113, s. 231-238
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Tidskriftsartikel (refereegranskat)abstract
- Tuberculosis has been reaffirmed as the infectious disease causing most deaths in the world. Co-infection with HIV and the increase in multi-drug resistant Mycobacterium tuberculosis strains complicate treatment and increases mortality rates, making the development of new drugs an urgent priority. In this study we have identified a promising candidate by screening antimicrobial peptides for their capacity to inhibit mycobacterial growth. This non-toxic peptide, NZX, is capable of inhibiting both clinical strains of M. tuberculosis and an MDR strain at therapeutic concentrations. The therapeutic potential of NZX is further supported in vivo where NZX significantly lowered the bacterial load with only five days of treatment, comparable to rifampicin treatment over the same period. NZX possesses intracellular inhibitory capacity and co-localizes with intracellular bacteria in infected murine lungs. In conclusion, the data presented strongly supports the therapeutic potential of NZX in future anti-TB treatment.
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| 6. |
- Alaridah, Nader, et al.
(författare)
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Mycobacteria Manipulate G-Protein-Coupled Receptors to Increase Mucosal Rac1 Expression in the Lungs
- 2017
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 9, s. 318-329
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Tidskriftsartikel (refereegranskat)abstract
- Mycobacterium bovis bacille Calmette-Guérin (BCG) is currently the only approved vaccine against tuberculosis (TB). BCG mimics M. tuberculosis (Mtb) in its persistence in the body and is used as a benchmark to compare new vaccine candidates. BCG was originally designed for mucosal vaccination, but comprehensive knowledge about its interaction with epithelium is currently lacking. We used primary airway epithelial cells (AECs) and a murine model to investigate the initial events of mucosal BCG interactions. Furthermore, we analysed the impact of the G-protein-coupled receptors (GPCRs), CXCR1 and CXCR2, in this process, as these receptors were previously shown to be important during TB infection. BCG infection of AECs induced GPCR-dependent Rac1 up-regulation, resulting in actin redistribution. The altered distribution of the actin cytoskeleton involved the MAPK signalling pathway. Blocking of the CXCR1 or CXCR2 prior to infection decreased Rac1 expression, and increased epithelial transcriptional activity and epithelial cytokine production. BCG infection did not result in epithelial cell death as measured by p53 phosphorylation and annexin. This study demonstrated that BCG infection of AECs manipulated the GPCRs to suppress epithelial signalling pathways. Future vaccine strategies could thus be improved by targeting GPCRs.
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| 7. |
- Damber, Jan-Erik, et al.
(författare)
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Rhythmical oscillations in rat testicular microcirculation as recorded by laser Doppler flowmetry
- 1983
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 118:2, s. 117-123
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Tidskriftsartikel (refereegranskat)abstract
- We have earlier reported that local testicular blood flow, recorded by laser Doppler flowmetry, shows large oscillations with a frequency of 5-10 min-1. In the present study it is proposed that the recorded oscillations represent mainly local microvascular blood flow variations rather than variations in total testicular blood flow or tissue movements. The reasons for this are: (a) Blood flow simultaneously measured at two separate sites showed oscillations with different frequencies. (b) A local subcapsular injection of room-tempered saline under one probe site eradicated oscillations under that probe but not under another adjacent probe. (c) When the testicular capsule was split open, recordings of blood flow continued to show oscillations. (d) The amplitude of the oscillations was rather large (peak to peak value about 50% of mean flow value). No movements of the testicular surface were seen. A 20 min continuous infusion of 0.4 microgram/min noradrenaline did induce a decrease in plasma testosterone concentration, but did not change the mean blood flow. However, the oscillations nearly completely disappeared during the infusion period. The present study also shows that laser Doppler flowmetry is a versatile method and the rat testis provides a suitable organ in the study of the origin and functional importance of these oscillations
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| 8. |
- Damber, Jan-Erik, et al.
(författare)
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Testicular blood flow measured with a laser Doppler flowmeter : acute effects of catecholamines.
- 1982
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Ingår i: Acta Physiologica Scandinavica. - : Wiley. - 0001-6772 .- 1365-201X. ; 115:2, s. 209-215
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Tidskriftsartikel (refereegranskat)abstract
- Laser Doppler flowmetry was used to continuously measure testicular blood flow in rats. The method was found applicable on surgically exposed testes. Regular oscillations in blood flow, with a periodicity of 8.6 +/- 0.7 cycles per minute (mean +/- SD), were observed in recordings from 22 to 23 rats. Clamping of the testicular artery reduced the blood flow signal to background values. Effects of catecholamines administered into the tail artery on testicular blood flow together with systemic effects on mean arterial blood pressure and heart rate were measured. It was found that noradrenaline as well as adrenaline caused a significant decrease in blood flow when 10 micrograms was injected. Only noradrenaline decreased the blood flow when 1 microgram was given. The large oscillations detected in the blood flow recordings disappeared quickly when 10 or 1 micrograms of both hormones was administered. It was concluded that catecholamines can exert rapid effects on testicular blood flow
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| 9. |
- Orfanos, Ioannis, et al.
(författare)
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Age- and sex-specific prevalence of serious bacterial infections in febrile infants <= 60 days, in Sweden
- 2021
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Ingår i: Acta Paediatrica. - : Wiley. - 0803-5253 .- 1651-2227. ; 110:11, s. 3069-3076
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Tidskriftsartikel (refereegranskat)abstract
- Aim The aim of the study was to describe age- and sex-specific prevalence of serious bacterial infections (SBI: urinary tract infection, bacteraemia, meningitis) among febrile infants <= 60 days in Sweden. Methods This is a retrospective study in 4 Pediatric Emergency Departments from 2014 to 2017, in previously healthy, full-term infants <= 60 days with fever without a source. Results Of the 1,701 included infants, 214 (12.6%; 95% CI, 11.1-14.3) had an SBI. Urinary tract infection (UTI) was diagnosed in 196 (11.5%; 95% CI, 10.0-13.1) patients. In the <= 28 and 29-60 days age-groups, meningitis prevalence was 0.9% (95% CI, 0.3-2.0) and 0.3% (95% CI, 0.1-0.8), whereas bacteraemia prevalence was 3.2% (95% CI, 1.9-4.9) and 0.6% (95% CI, 0.2-1.3). The SBI prevalence was higher in boys 16.0% (95% CI, 13.8-18.5) than girls 8.0% (95% CI, 6.2-10.2; p<0.001), due to 2-fold higher UTI risk. The prevalence of meningitis in boys was 0.3% (95% CI, 0.1- 0.9) vs. 0.7% (95% CI, 0.2-1.6) in girls and of bacteraemia 1.8% (95% CI, 1.0-2.8) vs. 1.0% (95% CI, 0.4-2.0), respectively. Conclusions The total SBI prevalence was 12.6%, and UTI represented the vast majority. The prevalence of bacteraemia and meningitis was low, particularly in the 29-60 days age group, without significant difference between boys and girls.
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| 10. |
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