| 1. |
- Aklillu, Eleni, et al.
(författare)
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Association of MAOA gene functional promoter polymorphism with CSF dopamine turnover and atypical depression.
- 2009
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Ingår i: Pharmacogenetics and genomics. - 1744-6872. ; 19:4, s. 267-75
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Monoamine oxidase-A (MAO-A) is a key mitochondrial enzyme that metabolizes biogenic amine neurotransmitters such as dopamine and serotonin. Individuals with atypical depression (AD) are particularly responsive to treatment with MAO inhibitors (MAOIs). Biomarker tests are essential for prompt diagnosis of AD, and to identify those with an altered brain neurotransmitter metabolism who may selectively respond to MAOI therapy. METHODS: In a sample of 118 Scandinavian patients with treatment-resistant depression who are naive to MAOI therapy, we investigated the associations between a common MAOA functional promoter polymorphism (MAOA-uVNTR), cerebrospinal fluid (CSF) neurotransmitter metabolites, and AD susceptibility. The metabolites for dopamine (homovanillic acid, HVA), serotonin (5-hydroxyindoleacetic acid) and noradrenaline (3-methoxy-4-hydroxyphenylglycol) were measured in the CSF. RESULTS: AD was associated with the female sex and a higher HVA in CSF (P=0.008). The carriers of the MAOA-uVNTR short allele were significantly overrepresented among women with AD (P=0.005; odds ratio=4.76; 95% confidence interval=1.5-13.1; statistical power=80.0%). Moreover, the MAOA-uVNTR genotype significantly influenced the HVA concentration (P=0.01) and showed a strong trend in relation to 5-hydroxyindoleacetic acid concentration (P=0.057) in women. The mediational statistical analyses showed the CSF-HVA concentration as a key driver of the relationship between MAOA-uVNTR genotype and AD. CONCLUSION: The association of the MAOA-uVNTR with both susceptibility to AD and dopamine metabolite (HVA) concentration lends further biological plausibility for high MAO-A enzyme activity as a mechanistic factor for genetic predisposition to AD through altered dopamine turnover. Our observations provide new evidence on the in-vivo functional significance of the MAOA-uVNTR short allele as a high activity variant.
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| 2. |
- Barregård, Lars, 1948, et al.
(författare)
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Toxicokinetics of mercury after long-term repeated exposure to thimerosal-containing vaccine.
- 2011
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Ingår i: Toxicological sciences : an official journal of the Society of Toxicology. - : Oxford University Press (OUP). - 1096-0929. ; 120:2, s. 499-506
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Tidskriftsartikel (refereegranskat)abstract
- The preservative thimerosal contains ethyl mercury (EtHg). Concerns over possible toxicity have re-emerged recently due to its presence in (swine and other) flu vaccines. We examined the potential accumulation of mercury in adults given repeated injections of a thimerosal-preserved vaccine for many years. Fifteen female patients were recruited from an outpatient clinic running a clinical trial with repeated injections (1 ml every 3-4 weeks) of a staphylococcus toxoid vaccine containing 0.01% thimerosal to treat chronic fatigue syndrome. Fifteen untreated female patients with the same diagnoses served as controls. Blood samples were taken before injecting the vaccine, 1 day later, about 2 weeks later, and just before the next injection. In the 15 controls, samples were taken twice. Blood was analyzed for total mercury and EtHg. The toxicokinetics were assessed for each patient separately as well as with a population-based pharmacokinetic model. Total mercury in blood increased on Day 1 in all treated patients (median: 0.33, range: 0.17-1.3 μg/l), as did EtHg (median: 0.14 μg/l, range: 0.06-0.43 μg/l). After a few weeks, levels were back to normal and similar to those in controls. Levels of methyl mercury (MeHg; from fish consumption) were much higher than those of EtHg. After exclusion of an outlier, the mean half-life in a population-based model was 5.6 (95% CI: 4.8-6.3) days. The results indicate that mercury from thimerosal is not accumulated in blood in adults. This is in accordance with short half-lives and rapid metabolism of EtHg to inorganic mercury.
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| 3. |
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| 4. |
- Elfaitouri, A, et al.
(författare)
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Murine Gammaretrovirus Group G3 Was Not Found in Swedish Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:10
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Tidskriftsartikel (refereegranskat)abstract
- Background: The recent report of gammaretroviruses of probable murine origin in humans, called xenotropic murine retrovirus related virus (XMRV) and human murine leukemia virus related virus (HMRV), necessitated a bioinformatic search for this virus in genomes of the mouse and other vertebrates, and by PCR in humans. Results: Three major groups of murine endogenous gammaretroviruses were identified. The third group encompassed both exogenous and endogenous Murine Leukemia Viruses (MLVs), and most XMRV/HMRV sequences reported from patients suffering from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Two sensitive real-time PCRs for this group were developed. The predicted and observed amplification range for these and three published XMRV/HMRV PCRs demonstrated conspicuous differences between some of them, partly explainable by a recombinatorial origin of XMRV. Three reverse transcription real-time PCRs (RTQPCRs), directed against conserved and not overlapping stretches of env, gag and integrase (INT) sequences of XMRV/HMRV were used on human samples. White blood cells from 78 patients suffering from ME/CFS, of which 30 patients also fulfilled the diagnostic criteria for fibromyalgia (ME/CFS/FM) and in 7 patients with fibromyalgia (FM) only, all from the Gothenburg area of Sweden. As controls we analyzed 168 sera from Uppsala blood donors. We controlled for presence and amplifiability of nucleic acid and for mouse DNA contamination. To score as positive, a sample had to react with several of the XMRV/HMRV PCRs. None of the samples gave PCR reactions which fulfilled the positivity criteria. Conclusions: XMRV/HMRV like proviruses occur in the third murine gammaretrovirus group, characterized here. PCRs developed by us, and others, approximately cover this group, except for the INT RTQPCR, which is rather strictly XMRV specific. Using such PCRs, XMRV/HMRV could not be detected in PBMC and plasma samples from Swedish patients suffering from ME/CFS/FM, and in sera from Swedish blood donors.
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| 5. |
- Haghighi, S., et al.
(författare)
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Open-label study with the monoamine stabilizer (-)-OSU6162 in myalgic encephalomyelitis/chronic fatigue syndrome
- 2021
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Ingår i: Brain and Behavior. - : Wiley. - 2162-3279. ; 11:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives The purpose of the present study was to investigate the safety and tolerability of the monoaminergic stabilizer (-)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). In addition, a potential therapeutic effect of (-)-OSU6162 in ME/CFS was evaluated by means of observer-rated scales and self-assessment rating scales. Materials and Methods In the current study using an open-label single-arm design ME/CFS patient received treatment with (-)-OSU6162 during 12 weeks. The patients received the following doses of (-)-OSU6162: 15 mg b.i.d. during the first 4-week period, up to 30 mg b.i.d. during the second 4-week period and up to 45 mg b.i.d. during the third 4-week period, with follow-up visits after 16 and 20 weeks. Results Out of 33 included patients, 28 completed the 12 weeks treatment period. (-)-OSU6162 was well tolerated; only one patient discontinued due to an adverse event. Vital signs and physical examinations showed no abnormal changes. Blood analyses showed an increase in serum prolactin. Therapeutically, improvements were seen on the Clinical Global Impression of Change scale, the FibroFatigue scale, the Mental Fatigue Scale, the Fatigue Severity Scale, Beck Depression Inventory, and the Short Form 36 Health Survey Questionnaire. Conclusions (-)-OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health-related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo-controlled double-blind trials.
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| 7. |
- Nilsson, Marie, 1968, et al.
(författare)
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A randomised controlled trial of the monoaminergic stabiliser (−)-OSU6162 in treatment of myalgic encephalomyelitis/chronic fatigue syndrome
- 2018
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Ingår i: Acta Neuropsychiatrica. - : Cambridge University Press (CUP). - 0924-2708 .- 1601-5215. ; 30:3, s. 148-57
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Tidskriftsartikel (refereegranskat)abstract
- © Scandinavian College of Neuropsychopharmacology 2017 Objective: The monoaminergic stabiliser (−)-OSU6162 has in previous studies shown promising effects on mental fatigue after stroke and traumatic brain injury. This study investigated the safety and effectiveness of (−)-OSU6162 in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Methods: A total of 62 patients were randomly assigned to placebo or (−)-OSU6162. Primary outcomes were assessment on the mental fatigue scale (MFS) and the clinical global impression of change (CGI-C) scale. Secondary outcomes were results on the FibroFatigue scale (FF), the Beck Depression Inventory (BDI), the pain visual analogue scale and neuropsychological tests. Assessments were performed at baseline, after 1 and 2 weeks of treatment and at follow-up after 6 weeks. Results: MFS and CGI-C showed significant improvements for both treatment groups after treatment but not at follow-up; a similar pattern was seen for FF and BDI. However, significant differences between groups could not be demonstrated. On the other hand, correlation analyses showed a significant correlation between (−)-OSU6162 concentration and change in MFS, FF, and BDI score within the concentration interval 0.1–0.7 µM. Exploratory subgroup analyses showed a larger treatment effect with (−)-OSU6162 in improving MFS and FF symptoms in patients on antidepressant therapy compared to those without antidepressant treatment. Conclusion: (−)-OSU6162 was found to be safe and well tolerated. When analysing the entire material (−)-OSU6162 was not found to differ significantly from placebo in alleviating fatigue in ME patients but was superior to placebo in counteracting fatigue in a subgroup of ME patients who received concomitant pharmacological treatment for depression.
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| 8. |
- Regland, Björn, 1947, et al.
(författare)
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Response to vitamin B12 and folic acid in myalgic encephalomyelitis and fibromyalgia
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with myalgic encephalomyelitis (ME, also called chronic fatigue syndrome) may respond most favorably to frequent vitamin B12 injections, in vital combination with oral folic acid. However, there is no established algorithm for individualized optimal dosages, and rate of improvement may differ considerably between responders. Objective: To evaluate clinical data from patients with ME, with or without fibromyalgia, who had been on B12 injections at least once a week for six months and up to several years. Methods: 38 patients were included in a cross-sectional survey. Based on a validated observer's rating scale, they were divided into Good (n = 15) and Mild (n = 23) responders, and the two groups were compared from various clinical aspects. Results: Good responders had used significantly more frequent injections (p<0.03) and higher doses of B12 (p<0.03) for a longer time (p<0.0005), higher daily amounts of oral folic acid (p<0.003) in good relation with the individual MTHFR genotype, more often thyroid hormones (p<0.02), and no strong analgesics at all, while 70% of Mild responders (p<0.0005) used analgesics such as opioids, duloxetine or pregabalin on a daily basis. In addition to ME, the higher number of patients with fibromyalgia among Mild responders was bordering on significance (p<0.09). Good responders rated themselves as "very much" or "much" improved, while Mild responders rated "much" or "minimally" improved. Conclusions: Dose-response relationship and long-lasting effects of B12/folic acid support a true positive response in the studied group of patients with ME/fibromyalgia. It's important to be alert on co-existing thyroid dysfunction, and we suspect a risk of counteracting interference between B12/folic acid and certain opioid analgesics and other drugs that have to be demethylated as part of their metabolism. These issues should be considered when controlled trials for ME and fibromyalgia are to be designed. © 2015 Regland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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| 9. |
- Zachrisson, Olof, 1963
(författare)
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Fibromyalgia/chronic fatigue syndrome. Aspects on biology, treatment, and symptom evaluation
- 2002
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background. Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are prevalent clinical conditions of unknown aetiology with substantial comorbidity. The diagnoses are based on internationally established criteria. Women are more often affected. Immunological abnormalities have been implicated and the onset is sometimes related to infection. The objective was to evaluate the clinical effect of immune modulation with the staphylococcal vaccine Staphypan Berna (SB) in FM/CFS, to explore mechanisms of action and predictors of outcome, to develop a rating instrument and to provide case reports on a subgroup of CFS patients with genetically related folate deficiency. Methods. One hundred women with both FM and CFS were included in a 6-month randomised controlled trial of SB. The preparation was administered subcutaneously in doses of 0.1 to 1.0 mL at weekly intervals for 8 weeks and then in booster doses of 1.0 mL 4-weekly. Main outcome measures were proportion of responders on ratings and proportion of 'good responders', defined as patients with a symptom reduction of =50% from baseline. Withdrawal was evaluated. The staphylococcal antibody levels were measured in serum of patients. Nickel allergy and smoking habits were recorded and related to outcome of treatment. Rating data were also analysed in order to develop a new rating instrument for symptom evaluation. Results. The injection programme was well tolerated and 65% responded to active treatment. The placebo response was 18% (P < 0.001). Patients on active treatment were significantly more often 'good responders'. Impairment was found at withdrawal. A serological response was found to several staphylococcal antigens and a significant positive correlation between antibody levels and clinical effect was noted. In 204 women with FM/CFS, 52% were found to have nickel allergy and 28% were cigarette smokers. Outcome of SB treatment was poorer among nickel allergic patients, especially among concomitant cigarette-smokers. The new rating instrument assesses 12 symptoms. The inter-rater reliability was found to be high. In a subgroup of CFS patients with genetically related folate deficiency, treatment with folate led to normalised serum homocysteine, which parallelled clinical improvement. Conclusion. FM and CFS are related conditions that respond to immune modulation with a staphylococcal preparation. Data indicate a relation between antibody response and clinical effect. Nickel allergy is prevalent and predicts poor response to staphylococcal vaccine. The results support that FM/CFS patients have underlying immune dysfunctions.
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