Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study.

OBJECTIVES: Fibromyalgia (FM) is one of the most common chronic pain syndromes. Various pathogenetic mechanisms have been implicated but none is proven. Our scope was to determine if Intraepidermal Nerve Fiber Density (IENFD) is reduced in the skin of FM patients, as observed in patients with painful small fiber sensory neuropathy (SFSN). DESIGN, SETTING AND PARTICIPANTS: We prospectively studied 46 FM patients (5 men and 41 women), aged 29 to 76 (mean: 52.5) years, diagnosed according to the ACR 2010 criteria, and 34 controls (18 women and 16 men) aged 19 to 84 (mean: 31.7) years. IENFD was measured using published guidelines and immune markers were sought immunocytochemically. In 30 FM patients, pain intensity was assessed with the Neuropathic Pain Symptom Inventory (NPSI), a scale validated for neuropathic pain. RESULTS: 15 of 46 (32.6%) FM patients had reduced IENFD [range: 0.6-12.5 fibers/mm (mean: 4.83 SD: 2.5)], compared to healthy controls [2.8-11.5 fibers/mm (mean: 7.35, SD: 1.85)] (p<0.0001). No significant correlation was noticed between NPSI scores and IENFD. No difference in the Langerhans cells, the major Antigen Presenting Cells (APCs) in the epidermis, or in IL-6 staining, was noted between FM and controls. IENFD was equally reduced in a subset of FM patients who also had another autoimmune disease. CONCLUSION: This is one of the largest series of FM patients demonstrating a significant reduction of IENFD in their skin biopsies. The findings indicate that in a subset of FM patients, the pain syndrome is, at least partially, of neuropathic origin. Skin biopsy may prove a useful tool and a potential biomarker in future studies of FM patients.

Oxidative damage to plasma proteins in patients with chronic alcohol dependence: the effect of smoking.

BACKGROUND: Accumulating evidence implicates oxidative stress in ethanol-induced toxicity. Ethanol has been reported to be involved in oxidative damage, mostly in vitro, or in post mortem tissues, while biochemical abnormalities in the blood or serum are scanty or lacking. The aim of the present study was to examine the oxidative status of plasma proteins as markers of oxidative stress in subjects with chronic alcohol dependence (CAD). Since smoking has also been associated with oxidative stress this factor was also considered. PATIENTS AND METHODS: A total of 71 patients with CAD and 61 healthy volunteers of comparable age were included in the study. The protein carbonyl assay was carried out in plasma, as a reliable measure of general oxidative protein damage, in these two groups. RESULTS: Increased plasma protein carbonyls (PCs) were found in patients with CAD as compared with the control group [mean values (nmollmg protein): 4.73+/-1.46 and 3.62+/-0.91 respectively, p<0.000001]. Within the control group, smokers had higher PCs than the non-smokers, however this difference was of marginal significance [mean values (nmol/mg protein): 3.93+/-1.32 and 3.47+/-0.63, respectively]. The CAD group had significantly increased PCs compared with both the smoker and the non-smoker subgroups of the controls (p<0.001 and p<0.0001, respectively). Duration of alcohol consumption, daily alcohol intake, smoke load, folic acid and vitamin B12 levels did not correlate significantly with PC levels. CONCLUSION: The above results support the evidence for systemic oxidative stress in CAD, which must be attributed mainly to alcohol consumption, while smoking may act synergistically.

Immunocytochemical study of cytoskeletal proteins in centronuclear myopathies.

The developmental status of muscle fibers was investigated in three cases of myotubular myopathy: one infant with the X-linked recessive form and two adult brothers with the autosomal, probably recessive, form of the disease. The presence of the developmentally regulated proteins desmin, vimentin and dystrophin was investigated by immunocytochemistry with the use of monoclonal antibodies. In the X-linked case, intense immunolabelling for vimentin and desmin was observed in the nuclear area of a great number of muscle fibers, while a few others showed sarcoplasmic dystrophin immunolabelling or were dystrophin-negative. In the adult cases, strong desmin immunoreactivity was observed, but only a few fibers labelled for vimentin. Dystrophin sarcolemmal immunolabelling was normal, but in some fibers dystrophin was observed in the area of the central nucleus. These findings are supportive of a maturational arrest of muscle fibers in the X-linked cases and possibly indicative of a similar mechanism in the adult form of centronuclear myopathy in these patients.

The diagnostic value of cerebrospinal fluid tau protein in dementing and nondementing neuropsychiatric disorders.

Cerebrospinal fluid (CSF) total tau protein (tauT) is increased in Alzheimer's disease (AD) and may be of some help in the diagnostic work-up of demented patients. The aim of the present study was to investigate the diagnostic aid and the additional help (over that of clinical criteria) of tauT in different clinical situations. Double-sandwich enzyme-linked immunosorbent assay was used to quantify tauT in 61 healthy controls and 241 patients with various neuropsychiatric diseases. Our results suggest that CSF tauT offers significant additional information over that of clinical criteria of AD, for the discrimination of AD from normal aging, depression, synucleinopathy, and possibly vascular dementia. However, for the differential diagnosis from frontotemporal dementia, corticobasal ganglionic degeneration, and secondary dementia, the diagnostic value is inadequate.

Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations.

Hereditary inclusion body myopathy (HIBM) is an adult onset neuromuscular disorder associated with mutations in the gene UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE), whose product is the rate limiting bi-functional enzyme catalyzing the first two steps of sialic acid biosynthesis. Loss of GNE activity in HIBM is thought to impair sialic acid production and interfere with proper sialylation of glycoconjugates, but it remains unclear how such a defect would lead to muscle destruction and muscle weakness. Hypoglycosylation of alpha-dystroglycan, a central protein of the skeletal muscle dystrophin-glycoprotein complex, results in disturbed interactions with extracellular matrix proteins. This has recently been identified as the pathomechanism involved in several congenital muscular dystrophies. We examined the glycosylation status of alpha-dystroglycan in muscle biopsies of four HIBM patients of non-Iranian Jewish origin (one American, two Indians, and one Greek). Two of these patients carry novel compound heterozygous GNE mutations on exon 2 and exon 9. All four muscle biopsies showed absent or markedly reduced immunolabeling with two different antibodies (VIA4 and IIH6) to glycosylated epitopes of alpha-dystroglycan. Normal labeling was found using antibodies to the core alpha-dystroglycan protein, beta-dystroglycan, and laminin alpha-2. These findings resemble those found for other congenital muscular dystrophies, suggesting that HIBM may be a "dystroglycanopathy," and providing an explanation for the muscle weakness of patients with GNE mutations.