Role of polymorphisms of inducible nitric oxide synthases in idiopathic environmental intolerances

Research abstract:

Oxidative stress and inflammation play a pathogenetic role in idiopathic environmental intolerances (IEI), namely, multiple chemical sensitivity (MCS), fibromyalgia (FM), and chronic fatigue syndrome (CFS).

Given the reported association of nitric oxide synthase (NOS) gene polymorphisms with inflammatory disorders, we aimed to investigate the distribution of NOS2A -2.5 kb (CCTTT) n as well as Ser608Leu and NOS3 -786T>C variants and their correlation with nitrite/nitrate levels, in a study cohort including 170 MCS, 108 suspected MCS (SMCS), 89 FM/CFS, and 196 healthy subjects.

Patients and controls had similar distributions of NOS2A Ser608Leu and NOS3 -786T>C polymorphisms. Interestingly, the NOS3 -786TT genotype was
associated with increased nitrite/nitrate levels only in IEI patients.

We also found that the NOS2A -2.5 kb (CCTTT)11 allele represents a genetic determinant for FM/CFS, and the (CCTTT)16 allele discriminates MCS from SMCS patients. Instead, the (CCTTT)8 allele reduces by three-, six-, and tenfold, respectively, the risk for MCS, SMCS, and FM/CFS. Moreover, a short number of (CCTTT) repeats is associated with higher concentrations of nitrites/nitrates.

Here, we first demonstrate that NOS3 -786T>C variant affects nitrite/nitrate levels in IEI patients and that screening for NOS2A -2.5 kb (CCTTT) n polymorphism may be useful for differential diagnosis of various IEI.

Role of polymorphisms of inducible nitric oxide synthase and endothelial nitric oxide synthase in idiopathic environmental intolerances by Chiara De Luca, Agnese Gugliandolo, Carlo Calabrò, Monica Currò, Riccardo Ientile, Desanka Raskovic, Ludmila Korkina and Daniela Caccamo in Mediators of Inflammation, 24 March 2015 (open access journal).

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HPV vaccine is suspected cause of POTs

Research abstract:

BACKGROUND

Infections with human papilloma virus (HPV) can result in cervical, oropharyngeal, anal, and penile cancer and vaccination programs have been launched in many countries as a preventive measure.

We report the characteristics of a number of patients with a syndrome of orthostatic intolerance, headache, fatigue, cognitive dysfunction, and neuropathic pain starting in close relation to HPV vaccination.

METHODS

Patients were referred for orthostatic intolerance following HPV vaccination. Symptoms of autonomic dysfunction were quantified by standardised questionnaire. The diagnosis of postural orthostatic tachycardia syndrome (POTS) rested on finding a sustained heart rate increment of >30min-1 (>40min-1 in adolescents) or to levels >120min-1 during orthostatic challenge.

RESULTS

35 women aged 23.3±7.1 years participated. Twenty-five had a high level of physical activity before vaccination and irregular periods were reported by all patients not on treatment with oral contraception.

Serum bilirubin was below the lower detection limit in 17 patients. Twenty-one of the referred patients fulfilled the criteria for a diagnosis of POTS (60%, 95%CI 43-77%).

All patients had orthostatic intolerance, 94% nausea, 82% chronic headache, 82% fatigue, 77% cognitive dysfunction, 72% segmental dystonia, 68% neuropathic pain.

CONCLUSIONS

In a population referred for symptoms of orthostatic intolerance and other symptoms consistent with autonomic dysfunction that began in close temporal association with a quadrivalent HPV vaccination, we identified a 60% prevalence of POTS.

Further work is urgently needed to elucidate the potential for a causal link between the vaccine and circulatory abnormalities and to establish targeted treatment options for the affected patients.

Orthostatic intolerance and postural tachycardia syndrome as suspected adverse effects of vaccination against human papilloma virus, by LS Brinth LS, Pors AC Theibel, J Mehlsenin in Vaccine, 13 April 2015 [Epub ahead of print].

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Response to Vitamin B12 and folic acid in ME and FM

Research 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.

METHOD

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.

Response to Vitamin B12 and Folic Acid in Myalgic Encephalomyelitis and Fibromyalgia, by Björn Regland,Sara Forsmark, Lena Halaouate, Michael Matousek, Birgitta Peilot,  Olof Zachrisson, Carl-Gerhard Gottfries in PLOS One, 22 April 2015

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Effect of household tasks on people with chronic fatigue & their partners

Research abstract:

This study examined salivary cortisol levels in couples in which one member had unexplained chronic fatigue (CF). The couples completed questionnaires and seven household activities in a laboratory setting and provided salivary cortisol samples prior to and immediately after the activities, as well as again after completing additional questionnaires and debriefing.

The couples rated their interactions as similar to those at home, suggesting ecological validity, and patients with CF experienced the activities as involving more exertion than did their partners.

The multilevel model results indicated that patients with CF had overall lower cortisol levels and flatter slopes across repeated measurements than did their significant others. Patients’ and significant others’ cortisol concentrations were significantly associated with each other over time. Furthermore, significant others’ cortisol was associated with greater relationship satisfaction and greater observed rates of patients’ illness/pain behaviors per minute, but patients’ levels of cortisol were not associated with relationship variables.

This study is the first to examine cortisol in couples with CF; the results are discussed in terms of implications for future research.

Salivary cortisol responses to household tasks among couples with unexplained chronic fatigue by Karen B Schmaling, Joan M Romano, Mark P Jensen, Charles W Wilkinson, Sterling McPherson in Journal of Family Psychology, Vol 29(2), Apr 2015, 296-301

 

 

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CBT & GET in clinical practice

Research abstract:

BACKGROUND

Studies have reported that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET) are effective treatments for Chronic Fatigue Syndrome (CFS).

METHOD

One hundred and seventy-one patients undertook a course of either CBT (n = 116) or GET (n = 55) and were assessed on a variety of self-report measures at pre- and posttreatment and follow-up.

AIMS

In this paper we present analyses on treatment outcomes for CBT and GET in routine clinical practice and evaluate whether changes on subscales of the Metacognitions Questionnaire-30 (MCQ-30) predict fatigue severity independently of changes in other covariates, and across the two treatment modalities.

RESULTS

Both CBT and GET were equally effective at decreasing fatigue, anxiety, and depression, and at increasing physical functioning. Changes on the subscales of the MCQ-30 were also found to have a significant effect on fatigue severity independently of changes in other covariates and across treatment modalities.

CONCLUSIONS

The findings from the current study suggest that CFS treatment protocols for CBT and GET, based on those from the PACE trial, achieve similar to poorer outcomes in routine clinical practice as in a RCT.

Treatment Outcome and Metacognitive Change in CBT and GET for Chronic Fatigue Syndrome, by Bruce A. Fernie, Gabrielle Murphy, Adrian Wells, Ana V. Nikčević and Marcantonio M. Spada in Behavioural and Cognitive Psychotherapy, 21 April 2015.

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Pregabalin useful for chronic pain

Research abstract

Pregabalin is frequently prescribed for chronic non-cancer pain. No previous study has examined its off-label use.

Objectives: Our primary aim was to assess the proportion of patients taking pregabalin for conditions approved by Health Canada (“on-label”) and compare their perspectives on its use to those who use pregabalin for other conditions (“off-label”).

Methods: Patients who have used pregabalin within the past year were recruited from two registries of chronic non-cancer pain patients treated in tertiary care clinics: the Quebec Pain Registry and the Fibromyalgia Patients Registry. Data on the use of pregabalin and its perceived benefits were collected from the registries and from completed questionnaires.

Results: Out of 4339 screened chronic non-cancer pain patients, 355 (8.18%) met the study selection criteria. Three-quarters of them (268/355) used pregabalin for pain conditions not approved by Health Canada and were therefore regarded as off-label users. The most prevalent condition for pregabalin use was lumbar back pain (103/357; 28.85%). There were no significant differences between on- and off-label users in their perceived satisfaction from pregabalin therapy and its effect on function and quality of life. Among former users, the most prevalent reason for discontinuation was adverse effects, mainly dry mouth and weight gain.

Conclusions: We conclude that despite specific indications for pregabalin prescription, it is mainly used off-label, notably for low back pain. Nevertheless, off-label users were equally satisfied with its clinical effects. Although formal exploration of broader analgesic properties of pregabalin is warranted, treating heterogeneous chronic pain conditions with pregabalin may be legitimate.

Limitations: The main limitations of the study are patients’ low response rate, the recruitment of participants solely from a tertiary pain center and not from the general patients’ population and a possible recall bias that may have arisen from the retrospective nature of the study.

Pregabalin for chronic pain: does one medication fit all?, by Hili Giladi, Manon Choinière, Mary-Ann Fitzcharles, Mark A. Ware, Xianming Tan, and Yoram Shir in Current Medical Research & Opinion, Posted online April 13, 2015

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CFS & FM in sleep disorders

Research abstract:

Background:

Since chronic fatigue syndrome (CFS) and fibromyalgia (FM) often co-exist, some believe they reflect the same process, somatization. Against that hypothesis are data suggesting FM but not CFS was common in patients with sleep-disordered breathing (SDB). The presence of discrete case definitions for CFS and FM allowed us to explore rates of CFS alone, CFS with FM, and FM alone in SDB patients compared to those with sleep complaints that fulfilled criteria for insomnia.

Methods

Participants were 175 sequential patients with sleep-related symptoms (122 had SDB and 21 had insomnia) and 39 healthy controls. Diagnoses were made by questionnaires, tender point count, and rule out labs; sleepiness was assessed with Epworth Sleepiness Scale and mood with Beck Depression Inventory.

Results

Rates of CFS, FM or CFS + FM were high: 13% in SDB and 48% in insomnia. CFS occurred frequently in SDB and insomnia, but FM occurred frequently only in insomnia. SDB patients with CFS and/or FM had higher daytime sleepiness than those without these disorders.

Conclusion

CFS patients should complete Epworth scales, and sleep evaluation should be considered for those with scores ≥ 16 before receiving the diagnosis of CFS; the coexistence of depressed mood in these patients suggests some may be helped by treatment of their depression. That FM was underrepresented in SDB suggests FM and CFS may have different underlying pathophysiological causes.

Chronic fatigue syndrome and fibromyalgia in diagnosed sleep disorders: a further test of the ‘unitary’ hypothesis, by Slobodanka Pejovic, Benjamin H Natelson, Maria Basta0, Julio Fernandez-Mendoza, Fauzia Mahr and Alexandros N Vgontzas in BMC Neurology 2015, 15:53, 12 April 2015

 

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FM and CFS: underlying biology

Article abstract:

There is an increasing interest in understanding the biological mechanism underpinning fibromyalgia (FM) and chronic fatigue syndrome (CFS).

Despite the presence of mixed findings in this area, a few biological systems have been consistently involved, and the increasing number of studies in the field is encouraging. This chapter will focus on inflammatory and oxidative stress pathways and on the neuroendocrine system, which have been more commonly examined.

Chronic inflammation, together with raised levels of oxidative stress and mitochondrial dysfunction, has been increasingly associated with the manifestation of symptoms such as pain, fatigue, impaired memory, and depression, which largely characterise at least some patients suffering from CFS and FM.

Furthermore, the presence of blunted hypothalamic-pituitary-adrenal axis activity, with reduced cortisol secretion both at baseline and in response to stimulation tests, suggests a role for the hypothalamic-pituitary-adrenal axis and cortisol in the pathogenesis of these syndromes. However, to what extent these systems’ abnormalities could be considered as primary or secondary factors causing FM and CFS has yet to be clarified.

Fibromyalgia and chronic fatigue: the underlying biology and related theoretical issues, by GF Romano, S Tomassi, A Russell, V Mondelli, CM Pariante in Adv Psychosom Med. 2015;34:61-77 [Epub 2015 Mar 30]

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Muscle cell abnormalities in CFS: AMPK & IL6

Research abstract:

Background: Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.

Methods: Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.

Results: In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS.

However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.

Conclusion: EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome, by Audrey E. Brown, David E. Jones, Mark Walker, Julia L. Newton in PLOSone [Published: April 2, 2015]

Commentary by MERUK: Muscle cell abnormalities

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Mindfulness as effective as anti-depressants for depression

From the BBC website:
A mindfulness-based therapy could offer a “new choice for millions of people” with recurrent depression, a Lancet report suggests. Scientists tested it against anti-depressant pills for people at risk of relapse and found it worked just as well.

The therapy trains people to focus their minds and understand that negative thoughts may come and go. In England and Wales doctors are already encouraged to offer it.

Patients who have had recurrent clinical depression are often prescribed long-term anti-depressant drugs to help prevent further episodes. And experts stress that drug therapy is still essential for many.

In this study, UK scientists enrolled 212 people who were at risk of further depression on a course of mindfulness-based cognitive therapy (MBCT) while carefully reducing their medication. Patients took part in group sessions where they learned guided meditation and mindfulness skills.

The therapy aimed to help people focus on the present, recognise any early warning signs of depression and respond to them in ways that did not trigger further reoccurrences.

Researchers compared these results to 212 people who continued to take a full course of medication over two years. By the end of the study, a similar proportion of people had relapsed in both groups. And many in the MBCT group had been tapered off their medication.

Scientists say these findings suggest MBCT could provide a much-needed alternative for people who cannot or do not wish to take long-term drugs.
In their report, they conclude it “may be a new choice for millions of people with recurrent depression on repeat prescriptions.”

Nigel Reed, who took part in the study, added: “Mindfulness gives me a set of skills which I use to keep well in the long term. “Rather than relying on the continuing use of anti-depressants, mindfulness puts me in charge, allowing me to take control of my own future, to spot when I am at risk and to make the changes I need to stay well.”

‘Important findings’
Providing an independent comment on the study, Dr Gwen Adshead, of the Royal College of Psychiatrists, said: “These findings are important from the point of view of people living with depression who are trying to engage in their own recovery.

“And it provides evidence that MBCT is an intervention that primary care physicians should take seriously as an option.” But he cautioned the research does not suggest MBCT is useful for all types of depression; nor that it should replace anti-depressant treatment for people with severe disorders who have needed hospital treatment or are suicidal. And experts caution patients should only reduce their anti-depressant medication under medical supervision.

Prof Eduard Vieta, Professor of Psychiatry at the University of Barcelona, Spain, said there needed to be more studies to establish how effective MBCT might be.
Researchers say their next step is to tease out what the active ingredient in mindfulness therapy might be, and to check it compares favourably to other group-based approaches.

From: Depression: ‘Mindfulness-based therapy shows promise’, by Smitha Mundasad, Health reporter, BBC News, 21 April 2015

Research article: Effectiveness and cost-effectiveness of mindfulness-based cognitive therapy compared with maintenance antidepressant treatment in the prevention of depressive relapse or recurrence (PREVENT): a randomised controlled trial, by Dr Willem Kuyken et al in Lancet [Published Online: 20 April 2015]

Guardian article: New study shows mindfulness therapy can be as effective as antidepressants

NHS choices: Mindfulness ‘as good as drugs for preventing depression relapse’

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