Background: Pain is a common symptom in peripheral neuropathies. The factors determining why some peripheral neuropathies are painful and others are not are incompletely understood. Pro-inflammatory cytokines have been implicated to play a crucial role in the generation of pain. Objective: To investigate whether cytokine profiles differ between patients with painful or painless neuropathy. Methods: In this prospective study, we analyzed blood mRNA and protein levels of the pro-inflammatory cytokines interleukin-2 (IL-2) and tumor necrosis factor-α (TNF) and the anti-inflammatory cytokines IL-4 and IL-10 in 32 patients with painful neuropathy, 20 patients with painless neuropathy, and 38 healthy control subjects, using quantitative real-time PCR and ELISA. Results: Patients with a painful neuropathy had about twofold higher IL-2 mRNA ( p = 0.001) and TNF mRNA ( p p = 0.009) than healthy control subjects and about twofold higher IL-2 and TNF mRNA ( p = 0.03; p = 0.001) and protein levels ( p = 0.04; p = 0.04) than patients with painless neuropathy. In contrast, mRNA levels of the anti-inflammatory cytokine IL-10 were about twofold higher in patients with painless neuropathy than in patients with painful neuropathy ( p = 0.001) and controls ( p = 0.004). IL-4 protein levels were 20-fold higher in patients with painless neuropathy ( p p Conclusions: A pro-inflammatory cytokine profile seems to be associated with pain in the setting of a peripheral neuropathy, corroborating findings in animal models with experimental painful neuropathies. This may have implications for future treatment strategies.

Differential expression of cytokines in painful and painless neuropathies

The understanding of why and how proteins misfold and aggregate into amyloid fibrils has increased considerably during recent years. Central to amyloid formation is an increase in the frequency of the β-sheet structure, leading to hydrogen bonding between misfolded monomers and creating a fibril that is comparably resistant to degradation. Generation of amyloid fibrils is nucleation dependent, and once formed, fibrils recruit and catalyze the conversion of native molecules. In AA amyloidosis, the expression of cytokines, particularly interleukin 6, leads to overproduction of serum amyloid A (SAA) by the liver. A chronically high plasma concentration of SAA results in the aggregation of amyloid into cross-β-sheet fibrillar deposits by mechanisms not fully understood. Therefore, AA amyloidosis can be thought of as a consequence of long-standing inflammatory disease. This review summarizes current knowledge about AA amyloidosis. The systemic amyloidoses have been regarded as intractable conditions, but improvements in the understanding of fibril composition and pathogenesis over the past decade have led to the development of a number of different therapeutic approaches with promising results.

AA Amyloidosis: Pathogenesis and Targeted Therapy

Purpose of review To summarize the recent advances in aetiology, diagnostic assessment, and treatment of small fibre neuropathies. Recent findings New causes of small fibre neuropathy have been recognized and advances in neurophysiologic and neuropathologic techniques for investigating small fibres have been made, increasing the interest in this field. In particular, skin biopsy proved to be a sensitive method to diagnose small fibre neuropathy. It allows the detection of subclinical abnormalities of peripheral nerve function in patients with diabetes and tongue denervation in patients with burning mouth syndrome. This technique has also been used to demonstrate the neuroprotective effect of erythropoietin in experimental models of neuropathy. Among nonconventional neurophysiologic techniques for investigating small fibres, laser-evoked potential and contact heat-evoked potential stimulators have been developed and deserve particular interest. Several trials on neuropathic pain that is a typical feature of small fibre neuropathies have been performed and guidelines have recently been published. Summary Detection of small fibre impairment allows earlier diagnosis of neuropathy and could be used as an outcome measure in future regenerative neuropathy trials. Standardization of skin biopsy can have an important impact on clinical practice and research. Further studies are needed to assess the reliability of current neurophysiologic techniques for testing small fibre function in peripheral neuropathies and the correlation with well established neuropathologic examination.

Small fibre neuropathies.

(P^2.14 3 10 25 ). Renal involvement was associated with poor survival in patients with AA amyloidosis (P^0.011) and the presence of cardiac involvement was likely to be a risk factor for survival (P^0.062). The rate of the causes of death in respect to the category of infection, gastrointestinal diseases, and renal failure was higher in patients with AA amyloidosis than in those without amyloidosis, gastrointestinal diseases and renal failure. Cyclophosphamide was found to be superior to methotrexate in the management of RA patients with AA amyloidosis. Conclusion. Our data support the fact that homozygosity for the SAA1.3 allele is a univariate predictor of survival in addition to a risk factor for the association of AA amyloidosis adversely influencing the outcome in Japanese RA patients. Renal involvement is a pivotal clinical manifestation in the development of AA amyloidosis, as is likely to be cardiac involvement in AA amyloidosis secondary to RA.

/pdf/significance-of-saa1-3-allele-genotype-in-japanese-patients-45nbapv6fu.pdf

Significance of SAA1.3 allele genotype in Japanese patients with amyloidosis secondary to rheumatoid arthritis

Conformational diseases: Looking into the eyes

Background. More than 80 transthyretin (TTR) mutations have been described, most associated with amyloidosis. Peripheral neuropathy is the most common clinical presentation in TTR amyloidosis although the carpal tunnel syndrome (CTS) may be the first symptom and skin can be involved, as transthyretin amyloidosis is a systemic disease.Case report. The 78 year-old proband, belonging to a French family of Italian origin, presented with a 5 year history of peripheral neuropathy in the lower extremities. However, 15 years earlier he had had surgery for bilateral CTS. Amyloidosis was diagnosed on salivary gland and skin biopsies. Immunohistochemistry on skin biopsy was positive using anti-TTR. The proband has 10 siblings, 5 have CTS.Methods. SSCP and direct sequencing of exons 2, 3, and 4 of the TTR gene were done on DNAJ from the proband and his brother who had had CTS. To confirm the mutation a PCR-IMRA was done.Results. SSCP analysis of TTR exons 2, 3, and 4 did not suggest a mutation. Sequence analysis of T...

A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis.

A Hungarian family with familial amyloid polyneuropathy (FAP) was studied. The disease presented in two individuals with carpal tunnel syndrome in the fourth and fifth decades of life. The proband subsequently developed vitreous opacities requiring vitrectomy and now has evidence of cardiomyopathy. Single strand conformation polymorphism analysis and direct DNA sequencing revealed a variant AGC (serine) codon at amino acid position 84 of the amyloid precursor protein, transthyretin (TTR). The same single amino acid substitution in TTR was detected in an Indiana kindred with Swiss/German origin. Six individuals of the 11 tested being at risk for FAP proved to have the mutation in the present Hungarian kindred. This is the first description of this TTR gene mutation in Europe. Despite TTR gene haplotype analysis which suggests that the Hungarian and Indiana kindreds may have a common origin, no genealogical link has been identified between the families living in Indiana and Hungary.

Transthyretin mutation (serine 84) associated with familial amyloid polyneuropathy in a Hungarian family.

Serum amyloid A1 (SAAI), one of the two isotypes of acute phase SAA, is the predominant precursor to amyloid A (AA) protein, the chief constituent of fibrillar deposits in reactive (AA) amyloidosis. Prolonged hyperexpression of SAA protein accompanying chronic inflammation is critical to, but seems not to be sufficient for, the development of AA amyloidosis. Several previous studies have investigated the possibility of linkage between SAAI exon 3 polymorphisms and susceptibility to amyloidosis. While the SAAI. I allele was found to have a negative association with amylodosis in Japanese subjects, it showed a positive association in Caucasians. Moriguchi and colleagues recently showed that a single nucleotide polymorphism (SNP) at position -13 in the SAAl S' flanking region was more strongly associated with amyloidosis than was the exon 3 polymorphism. To test whether this SNP may be an amyloidogenic factor common to Japanese and Caucasians, we have analyzed the SAA l gene in amyloid and non-amyloid patien...

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians.

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A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis.

Transthyretin mutation (serine 84) associated with familial amyloid polyneuropathy in a Hungarian family.

An allele of serum amyloid A1 associated with amyloidosis in both Japanese and Caucasians.