A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia

<p>Abstract</p> <p>Background</p> <p>A consistent line of investigation suggests that autonomic nervous system dysfunction may explain the multi-system features of fibromyalgia (FM); and that FM is a sympathetically maintained neuropathic pain syndrome. Dorsal root ganglia (DRG) are key sympathetic-nociceptive short-circuit sites. Sodium channels located in DRG (particularly Nav1.7) act as molecular gatekeepers for pain detection. Nav1.7 is encoded in gene SCN9A of chromosome 2q24.3 and is predominantly expressed in the DRG pain-sensing neurons and sympathetic ganglia neurons. Several SCN9A sodium channelopathies have been recognized as the cause of rare painful dysautonomic syndromes such as paroxysmal extreme pain disorder and primary erythromelalgia. The aim of this study was to search for an association between fibromyalgia and several SCN9A sodium channels gene polymorphisms.</p> <p>Methods</p> <p>We studied 73 Mexican women suffering from FM and 48 age-matched women who considered themselves healthy. All participants filled out the Fibromyalgia Impact Questionnaire (FIQ). Genomic DNA from whole blood containing EDTA was extracted by standard techniques. The following SCN9A single-nucleotide polymorphisms (SNP) were determined by 5' exonuclease TaqMan assays: rs4371369; rs4387806; rs4453709; rs4597545; rs6746030; rs6754031; rs7607967; rs12620053; rs12994338; and rs13017637.</p> <p>Results</p> <p>The frequency of the rs6754031 polymorphism was significantly different in both groups (<it>P </it>= 0.036) mostly due to an absence of the GG genotype in controls. Interestingly; patients with this rs6754031 GG genotype had higher FIQ scores (median = 80; percentile 25/75 = 69/88) than patients with the GT genotype (median = 63; percentile 25/75 = 58/73; <it>P </it>= 0.002) and the TT genotype (median = 71; percentile 25/75 = 64/77; <it>P </it>= 0.001).</p> <p>Conclusion</p> <p>In this ethnic group; a disabling form of FM is associated to a particular SCN9A sodium channel gene variant. These preliminary results raise the possibility that some patients with severe FM may have a dorsal root ganglia sodium channelopathy.</p

Norepinephrine-evoked pain in fibromyalgia. A randomized pilot study [ISRCTN70707830]

BACKGROUND: Fibromyalgia syndrome displays sympathetically maintained pain features such as frequent post-traumatic onset and stimuli-independent pain accompanied by allodynia and paresthesias. Heart rate variability studies showed that fibromyalgia patients have changes consistent with ongoing sympathetic hyperactivity. Norepinephrine-evoked pain test is used to assess sympathetically maintained pain syndromes. Our objective was to define if fibromyalgia patients have norepinephrine-evoked pain. METHODS: Prospective double blind controlled study. Participants: Twenty FM patients, and two age/sex matched control groups; 20 rheumatoid arthritis patients and 20 healthy controls. Ten micrograms of norepinephrine diluted in 0.1 ml of saline solution were injected in a forearm. The contrasting substance, 0.1 ml of saline solution alone, was injected in the opposite forearm. Maximum local pain elicited during the 5 minutes post-injection was graded on a visual analog scale (VAS). Norepinephrine-evoked pain was diagnosed when norepinephrine injection induced greater pain than placebo injection. Intensity of norepinephrine-evoked pain was calculated as the difference between norepinephrine minus placebo-induced VAS scores. RESULTS: Norepinephrine-evoked pain was seen in 80 % of FM patients (95% confidence intervals 56.3 – 94.3%), in 30 % of rheumatoid arthritis patients and in 30 % of healthy controls (95% confidence intervals 11.9 – 54.3) (p < 0.05). Intensity of norepinephrine-evoked pain was greater in FM patients (mean ± SD 2.5 ± 2.5) when compared to rheumatoid arthritis patients (0.3 ± 0.7), and healthy controls (0.3 ± 0.8) p < 0.0001. CONCLUSIONS: Fibromyalgia patients have norepinephrine-evoked pain. This finding supports the hypothesis that fibromyalgia may be a sympathetically maintained pain syndrome

Mitochondrial myopathy presenting as fibromyalgia: a case report

<p>Abstract</p> <p>Introduction</p> <p>To the best of our knowledge, we describe for the first time the case of a woman who met the diagnostic criteria for fibromyalgia, did not respond to therapy for that disorder, and was subsequently diagnosed by biochemical and genetic studies with a mitochondrial myopathy. Treatment of the mitochondrial myopathy resulted in resolution of symptoms. This case demonstrates that mitochondrial myopathy may present in an adult with a symptom complex consistent with fibromyalgia.</p> <p>Case presentation</p> <p>Our patient was a 41-year-old Caucasian woman with symptoms of fatigue, exercise intolerance, headache, and multiple trigger points. Treatment for fibromyalgia with a wide spectrum of medications including non-steroidal anti-inflammatory drugs, antidepressants, gabapentin and pregabalin had no impact on her symptoms. A six-minute walk study demonstrated an elevated lactic acid level (5 mmol/L; normal < 2 mmol/L). Biochemical and genetic studies from a muscle biopsy revealed a mitochondrial myopathy. Our patient was started on a compound of coenzyme Q10 (ubiquinone) 200 mg, creatine 1000 mg, carnitine 200 mg and folic acid 1 mg to be taken four times a day. She gradually showed significant improvement in her symptoms over a course of several months.</p> <p>Conclusions</p> <p>This case demonstrates that adults diagnosed with fibromyalgia may have their symptom complex related to an adult onset mitochondrial myopathy. This is an important finding since treatment of mitochondrial myopathy resulted in resolution of symptoms.</p

Sarcoptic mange in wild ruminants in Spain: solving the epidemiological enigma using microsatellite markers

Background: In Spain, sarcoptic mange was first described in native wildlife in 1987 in Cazorla Natural Park, causing the death of nearly 95% of the local native population of Iberian ibex (Capra pyrenaica). Since then, additional outbreaks have been identified in several populations of ibex and other wild ungulate species throughout the country. Although the first epizootic outbreak in wildlife was attributed to the introduction of an infected herd of domestic goats, the origin and the cause of its persistence remain unclear. The main aims of this study are to understand (i) the number of Sarcoptes scabiei “strains” circulating in wild ruminant populations in Spain, and (ii) the molecular epidemiological relationships between S. scabiei and its hosts. Methods: Ten Sarcoptes microsatellite markers were used to characterize the genetic structure of 266 mites obtained from skin scrapings of 121 mangy wild ruminants between 2011 and 2019 from 11 areas in Spain. Results: Seventy-three different alleles and 37 private alleles were detected. The results of this study show the existence of three genetic strains of S. scabiei in the wild ruminant populations investigated. While two genetic clusters of S. scabiei were host- and geography-related, one cluster included multi-host mites deriving from geographically distant populations. Conclusions: The molecular epidemiological study of S. scabiei in wild ruminants in Spain indicates that the spreading and persistence of the parasite may be conditioned by host species community composition and the permissiveness of each host population/community to the circulation of individual “strains,” among other factors. Wildlife–livestock interactions and the role of human-driven introduction or trade of wild and domestic animals should be better investigated to prevent further spread of sarcoptic mange in as yet unaffected natural areas of the Iberian Peninsula

Dopamine Innervation in the Thalamus: Monkey versus Rat

We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT) in adult macaque and rat brains. The extent and density of DAT-immunoreactive (-ir) axons were remarkably greater in the macaque dorsal thalamus, where the mediodorsal association nucleus and the ventral motor nuclei held the densest immunolabeling. In contrast, sparse DAT immunolabeling was present in the rat dorsal thalamus; it was mainly located in the mediodorsal, paraventricular, ventral medial, and ventral lateral nuclei. The reticular nucleus, zona incerta, and lateral habenular nucleus held numerous DAT-ir axons in both species. Ultrastructural analysis in the macaque mediodorsal nucleus revealed that thalamic interneurons are a main postsynaptic target of DAT-ir axons; this suggests that the marked expansion of the dopamine innervation in the primate in comparison to the rodent thalamus may be related to the presence of a sizable interneuron population in primates. We remark that it is important to be aware of brain species differences when using animal models of human brain disease

Factors explaining variance in perceived pain in women with fibromyalgia

BACKGROUND: We hypothesized that a substantial proportion of the subjectively experienced variance in pain in fibromyalgia patients would be explained by psychological factors alone, but that a combined model, including neuroendocrine and autonomic factors, would give the most parsimonious explanation of variance in pain. METHODS: Psychometric assessment included McGill Pain Questionnaire, General Health Questionnaire, Hospital Anxiety and Depression Rating Scale, Eysenck personality Inventory, Neuroticism and Lie subscales, Toronto Alexithymia Scale, and Multidimensional Health Locus of Control Scale and was performed in 42 female patients with fibromyalgia and 48 female age matched random sample population controls. A subgroup of the original sample (22 fibromyalgia patients and 13 controls) underwent a pharmacological challenge test with buspirone to assess autonomic and adrenocortical reactivity to serotonergic challenge. RESULTS: Although fibromyalgia patients scored high on neuroticism, anxiety, depression and general distress, only a minor part of variance in pain was explained by psychological factors alone. High pain score was associated with high neuroticism, low baseline cortisol level and small drop in systolic blood pressure after buspirone challenge test. This model explained 41.5% of total pain in fibromyalgia patients. In population controls, psychological factors alone were significant predictors for variance in pain. CONCLUSION: Fibromyalgia patients may have reduced reactivity in the central sympathetic system or perturbations in the sympathetic-parasympathetic balance. This study shows that a biopsychosocial model, including psychological factors as well as factors related to perturbations of the autonomic nervous system and hypothalamic-pituitary-adrenal axis, is needed to explain perceived pain in fibromyalgia patients

Lung carcinoma with hypertrophic osteoarthropathy in a teenager

Hypertrophic osteoarthropathy (HOA) characterised by arthralgia, clubbing and periosteal proliferation of long bones, is rarely encountered in children and adolescents. Whereas in adults over 80% of cases are associated with malignancy, in children the majority of cases are due to non-neoplastic causes such as cystic fibrosis, bilary atresia and congenital heart disease. Up to 5% of adults with lung cancer demonstrate signs of HOA. However, lung cancer is extremely uncommon in children and young people. Here we report a case of lung adenocarcinoma in an 18 year old male associated with HOA present both at diagnosis and at subsequent disease progression

Gastric Juvenile Polyposis with High-Grade Dysplasia in Pachydermoperiostosis

Pachydermoperiostosis (PDP) is the primary form of hypertrophic osteoarthropathy. It is a very rare disease consisting of pachydermia, digital clubbing and radiologic periostosis. Various digestive symptoms in PDP are seen in 11–49% of patients and juvenile polyps may be found at gastric endoscopy. We report here the history of a patient with PDP who was referred for assessment of severe anemia. Endoscopy of the upper digestive tract showed multiple polyps of the stomach with two huge lesions exhibiting foci of high-grade dysplasia. This observation suggests that PDP can be considered as a precancerous condition of the stomach and systematic screening using endoscopy should be considered in these patients

The diagnosis and management of neuropathic pain in daily practice in Belgium: an observational study

<p>Abstract</p> <p>Background</p> <p>This open, multicentre, observational survey investigated how physicians diagnose neuropathic pain (NeP) by applying the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale, and how neuropathic pain conditions are managed in daily practice in Belgium.</p> <p>Methods</p> <p>Physicians were asked to complete the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale for diagnosing NeP, and to fill out a questionnaire regarding the management of NeP, together with a questionnaire evaluating the impact of pain on sleep and daily life. Data on 2,480 pain patients were obtained. A LANSS score ≥ 12 (meaning NeP is most probably present) was reported for 1,163 patients. Pathologies typically associated with NeP scored above 12 on the LANSS scale, contrary to pathologies generally considered as being of non-neuropathic origin.</p> <p>Results</p> <p>Over 90% of the patients with a LANSS score ≥ 12 reported that the pain impaired sleep. A high impact on social, family and professional life was also recorded. Additional examinations were performed in 89% of these patients. Most patients were taking multiple drugs, mainly paracetamol and non-steroidal anti-inflammatory drugs, indicating that physicians generally tend to follow treatment guidelines of chronic nociceptive pain, rather than the specific ones for NeP. Specific neuropathic guidelines rather recommend the use of anti-epileptic drugs, tricyclic antidepressants or weak opioids as first-line treatment.</p> <p>Conclusion</p> <p>In our survey, application of the LANSS scale lead to pronounced treatment simplification with fewer drug combinations. Awareness about NeP as well as its specific treatment recommendations should be raised among healthcare providers. We concluded that the LANSS screening scale is an interesting tool to assist physicians in detecting NeP patients in routine clinical care.</p

Measurement of the Branching Fraction for B- --> D0 K*-

We present a measurement of the branching fraction for the decay B- --> D0 K*- using a sample of approximately 86 million BBbar pairs collected by the BaBar detector from e+e- collisions near the Y(4S) resonance. The D0 is detected through its decays to K- pi+, K- pi+ pi0 and K- pi+ pi- pi+, and the K*- through its decay to K0S pi-. We measure the branching fraction to be B.F.(B- --> D0 K*-)= (6.3 +/- 0.7(stat.) +/- 0.5(syst.)) x 10^{-4}.Comment: 7 pages, 1 postscript figure, submitted to Phys. Rev. D (Rapid Communications