Management of Plantar Hyperhidrosis with Endoscopic Lumbar Sympathectomy.

Primary plantar hyperhidrosis is defined as excessive secretion of the sweat glands of the feet and may lead to significant limitations in private and professional lifestyle and reduction of health-related quality of life. Conservative therapy measures usually fail to provide sufficient relieve of symptoms and do not allow long-lasting elimination of hyperhidrosis. Endoscopic lumbar sympathectomy appears to be a safe and effective procedure for eliminating excessive sweating of the feet and improves quality of life of patients with severe plantar hyperhidrosis.

Quality of life after endoscopic lumbar sympathectomy for primary plantar hyperhidrosis.

BACKGROUND: Primary plantar hyperhidrosis is characterised by excessive secretion of the sweat glands of the feet and may lead to significant limitations in private and professional lifestyle. The aim of this prospective study was to assess the effect of endoscopic lumbar sympathectomy (ESL) on the quality of life (QL) of patients with primary plantar hyperhidrosis. METHODS: Bilateral ESL was performed on 52 patients, 31 men and 21 women with primary plantar hyperhidrosis. Perioperative morbidity and clinical results were evaluated in all patients after a mean follow-up of 15 months. Postoperative QL was examined with the SF-36V2 questionnaire and the hyperhidrosis-specific questionnaires devised by Milanez de Campos and Keller. RESULTS: All procedures were carried out endoscopically with no perioperative morbidity. Plantar hyperhidrosis was eliminated in 50 patients (96%) and two patients (4%) suffered a relapse. Unwanted side effects occurred in the form of compensatory sweating in 34 (65%) and in the form of postsympathectomy neuralgia in 19 patients (37%). Ninety six percentage of patients were satisfied with the postoperative result and 88% would have the surgery repeated. The SF-36V2 questionnaire revealed a significant improvement of QL after lumbar sympathectomy in physical health (physical component summary, p < 0.01) as well as mental health (mental component summary, p < 0.05). Improved QL was also demonstrated in the Milanez de Campos questionnaire in the dimensions functionality/social interactions (p < 0.01), intimacy (p < 0.01), emotionality (p < 0.01) and specific circumstances (p < 0.01) as well as in the Keller questionnaire in the area of plantar hyperhidrosis (p < 0.01). CONCLUSION: The performance of an ESL in patients with primary plantar hyperhidrosis leads to the effective elimination of excessive sweat secretion of the feet and to an increase in QL.

Endoscopic lumbar sympathectomy following thoracic sympathectomy in patients with palmoplantar hyperhidrosis.

BACKGROUND: Palmoplantar hyperhidrosis is a common disease that leads to significant psychosocial strain for the affected person. Although the treatment of palmar symptoms with endoscopic thoracic sympathectomy (ETS) is clinically established, there are few data on the efficacy of an endoscopic lumbar sympathectomy (ELS) for the elimination of plantar symptoms. Especially the occurrence of unwanted side effects associated with sequential ETS and ELS has not been examined sufficiently. METHODS: The study includes 130 patients, 8 men and 122 women, with severe palmoplantar hyperhidrosis who were already previously treated with ETS. An average of 28 months after the ETS, bilateral ELS was performed on all patients due to persistent severe plantar hyperhidrosis. After ELS the perioperative morbidity, elimination rate of the plantar hyperhidrosis, the frequency of unwanted side effects, and satisfaction with the result were evaluated. Follow-up examinations were carried out on 96 patients (74%) with a mean follow-up of 37 months (3-90 months). RESULTS: A total of 260 lumbar sympathectomies were successfully carried out endoscopically. Mortality was zero, intraoperative complications occurred in three (2.3%) patients and postoperative complications in six (4.6%). Plantar hyperhidrosis was eliminated in 93 patients (97%), 3 (3%) patients developed a one-sided recurrence. Seven patients (7%) developed minor compensatory sweating, and in 17 patients (18%) compensatory sweating that existed before the ELS was slightly increased. Transient postsympathectomy neuralgia was observed in 18 patients (19%), and none of the patients showed a sexual function disorder. Altogether, 77 patients (80%) were very satisfied with the postoperative result, and 16 (17%) were partially satisfied. CONCLUSIONS: The sesequential performance of ELS after ETS appears to be a safe, effective therapy option for patients with severe palmoplantar hyperhidrosis. However, more experience with a larger number of patients and longer follow-up investigations are necessary to confirm the safety of four-limb sympathectomy.

The X and why of xenobiotics in primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic autoimmune liver disease characterized by inflammation and destruction of intrahepatic biliary epithelial cells, ultimately leading to liver failure. The serological hallmark of PBC is the presence of high-titer antimitochondrial antibodies (AMA) against the inner lipoyl domain of E2 subunits of 2-oxo-acid dehydrogenase complexes, in particular the E2 component of the pyruvate dehydrogenase complex (PDC-E2). The initiating events triggering the autoimmune response are not yet identified but the hypothesis of molecular mimicry is a widely proposed mechanism for the development of autoimmunity in PBC. Several candidates, including bacteria and viruses, have been suggested as causative agents, but also environmental factors, such as chemical xenobiotics, have been implicated in the pathogenesis of primary biliary cirrhosis. In this review, we will discuss our current knowledge of the immunoreactivity of xenobiotically modified PDC peptide antigens. In addition, we will provide a working hypothesis how xenobiotic modification of antigens might occur that ultimately leads to the breaking of self-tolerance and the induction of PBC.

A sensitive bead assay for antimitochondrial antibodies: Chipping away at AMA-negative primary biliary cirrhosis.

UNLABELLED: The antimitochondrial response in primary biliary cirrhosis (PBC) is the most highly directed and specific self-reacting antibody in human immunopathology. Originally, antimitochondrial antibodies (AMAs) were detected by indirect immunofluorescence (IIF) and found in approximately 90% of well-documented patients with PBC. The introduction of recombinant autoantigens and the use of immunoblotting have increased the sensitivity and specificity of AMAs, and they are now considered positive in approximately 95% of patients with PBC. Clearly, accurate autoantibody detection represents one of the fundamental requirements for reliable diagnostics in autoimmunity. To address the 5% of AMA-negative patients with PBC, we have generated and validated a bead assay for the detection of AMA. We enrolled 120 patients with PBC, including a non-random group of 30 rigorously proven AMA-negative patients, 50 healthy subjects, and 74 controls with autoimmune diseases (18 with primary sclerosing cholangitis, 16 with autoimmune hepatitis, and 40 with systemic lupus erythematosus). Individual bead assays were done with the three mitochondrial autoantigens, PDC-E2, BCOADC-E2, and OGDC-E2. As expected, 90 of 90 previously known AMA-positive patients remained positive with this assay but, interestingly, 20% of the rigorously defined AMA-negative patient group had antibodies to one or more of the mitochondrial autoantigens. Furthermore, 100% of these newly detected AMA-positive patients were anti-nuclear antibody (ANA) positive. CONCLUSION: The development of this assay reflects the potential for automated detection with rapid and reliable assaying and further highlights the diminished number of truly AMA-negative PBC patients.

Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis.

Antimitochondrial antibodies (AMA) are unique among autoimmune serologic reactants because of their extremely high association with the index disease primary biliary cirrhosis (PBC). This autoantibody response is specifically directed only to the lipoyl domain of the mitochondrial 2-oxo-acid dehydrogenase complexes, which prompted us to search for environmental mimotopes in the form of xenobiotics and led to our identification of 2-octynoic acid as a high-affinity reactant for AMA. To focus on the chemical characteristics requisite for binding of AMA to the xenobiotic-modified self-peptide, quantitative structure-activity relationship (QSAR) studies were performed using a panel of alkynoic compounds, including examination of the length of the carbon chain and the location of the triple bond in the identified mimotope. Analyses of octynamides that varied in the position of the triple bond demonstrated that only the 2-octynamide reacted strongly with PBC sera. Furthermore, among 2-alkynamides with varying carbon chain length, 2-octyn-, 2-nonyn- (particularly) and 2-decynamide exhibited the highest reactivity. Thus, an optimal chemical structure of the xenobiotically modified epitope recognized by AMA-positive PBC sera is provided by 2-nonynoic acid. The methyl ester of this compound is ranked 2,324th out of 12,945 compounds to which there is occupational exposure, with an 80% female prevalence due to its use in cosmetic products. Our findings illustrate an unusual polyreactivity of anti-PDC-E2 and support the idea of epitope mimicry in the genesis of this autoantibody and perhaps of PBC itself.

Decreased serum leptin levels in primary biliary cirrhosis: a link between metabolism and autoimmunity?

Primary biliary cirrhosis (PBC) is an autoimmune liver disease of unknown etiology resulting in the progressive destruction of the intrahepatic bile ducts and leading to chronic cholestasis and ultimately liver cirrhosis and failure. The immune response in PBC seems to be mediated by autoantibodies as well as autoreactive T lymphocytes directed against mitochondrial antigens in biliary epithelial cells, primarily PDC-E2. Experimental evidence suggests a role of the hormone/cytokine leptin in autoimmune diseases. Leptin is an adipocyte-derived molecule that acts as a hormone influencing food intake and energy metabolism as well as a cytokine with pro-inflammatory, immune-regulatory functions. To study serum leptin in PBC and its association with disease severity, we evaluated serum levels in 37 patients with PBC (27 with no signs of fibrosis or cirrhosis at histologic examination) and 37 age- and sex-matched healthy controls using a validated ELISA method. We found that patients with PBC had significantly lower leptin serum levels compared with healthy controls (13.6 +/- 13.8 vs. 17.6 +/- 11.6; P < 0.05). No correlation between disease severity and serum leptin levels was found. This study has demonstrated that leptin levels are decreased in the serum of patients with PBC but do not seem to be associated with disease severity. Data do not seem to indicate a direct role of leptin in the perpetuation of the autoimmune response in PBC. However, further studies are warranted to further characterize the functions of leptin during the natural history of autoimmunity.

Chemical xenobiotics and mitochondrial autoantigens in primary biliary cirrhosis: identification of antibodies against a common environmental, cosmetic, and food additive, 2-octynoic acid.

Emerging evidence has suggested environmental factors as causative agents in the pathogenesis of primary biliary cirrhosis (PBC). We have hypothesized that in PBC the lipoyl domain of the immunodominant E2 component of pyruvate dehydrogenase (PDC-E2) is replaced by a chemical xenobiotic mimic, which is sufficient to break self-tolerance. To address this hypothesis, based upon our quantitative structure-activity relationship data, a total of 107 potential xenobiotic mimics were coupled to the lysine residue of the immunodominant 15 amino acid peptide of the PDC-E2 inner lipoyl domain and spotted on microarray slides. Sera from patients with PBC (n = 47), primary sclerosing cholangitis (n = 15), and healthy volunteers (n = 20) were assayed for Ig reactivity. PBC sera were subsequently absorbed with native lipoylated PDC-E2 peptide or a xenobiotically modified PDC-E2 peptide, and the remaining reactivity analyzed. Of the 107 xenobiotics, 33 had a significantly higher IgG reactivity against PBC sera compared with control sera. In addition, 9 of those 33 compounds were more reactive than the native lipoylated peptide. Following absorption, 8 of the 9 compounds demonstrated cross-reactivity with lipoic acid. One compound, 2-octynoic acid, was unique in both its quantitative structure-activity relationship analysis and reactivity. PBC patient sera demonstrated high Ig reactivity against 2-octynoic acid-PDC-E2 peptide. Not only does 2-octynoic acid have the potential to modify PDC-E2 in vivo but importantly it was/is widely used in the environment including perfumes, lipstick, and many common food flavorings.

CpG oligodeoxynucleotides enhance the capacity of adenovirus-mediated CD154 gene transfer to generate effective B-cell lymphoma vaccines.

Activation of CD40 by CD154 induces antigen-presenting cells (APC) to express immune costimulatory molecules, thereby enhancing their APC activity. Oligonucleotides (ODN), containing immunostimulatory DNA sequences (ISS) with nonmethylated CpG dinucleotides in a defined motif, also can induce similar changes in APC. In this study, we examined whether infection with recombinant adenovirus (Ad) encoding CD154 and/or treatment with ISS-ODN could enhance the capacity of A20 murine B lymphoma cells to function as APCs capable of inducing a syngeneic antilymphoma immune response. High-level expression of CD154 after infection with Ad-CD154 induced up-regulation of immune costimulatory molecules on A20 cells, as did incubation with ISS-ODN. Treatment of A20 cells with ISS-ODN also enhanced surface expression of alphav integrins, making them significantly more susceptible to Ad infection than nontreated A20 cells. In syngeneic mixed-lymphocyte reactions with BALB/c splenocytes, A20 cells activated with ISS-ODN and then transduced with Ad-CD154 were significantly more effective APCs than Ad-CD154 transduced cells, which, in turn, were significantly more effective than A20 cells treated with ISS-ODN alone. Also, injection of mice with ISS-activated, Ad-CD154-infected cells induced significantly better A20-specific immune responses against A20 cells, as assessed via enzyme-linked immunospot analysis in vitro and immune prophylaxis against subsequent challenge with A20 lymphoma cells in vivo. These data demonstrate that CpG-containing oligonucleotides can serve as an adjuvant for Ad-mediated gene therapy of B-cell malignancies.

The 37 kDa/67 kDa laminin receptor is required for PrP(Sc) propagation in scrapie-infected neuronal cells.

The accumulation of PrP(Sc) in scrapie-infected neuronal cells has been prevented by three approaches: (i) transfection of ScMNB cells with an antisense laminin receptor precursor (LRP) RNA-expression plasmid, (ii) transfection of ScN2a cells and ScGT1 cells with small interfering RNAs (siRNAs) specific for the LRP mRNA, and (iii) incubation of ScN2a cells with an anti-LRP/LR antibody. LRP antisense RNA and LRP siRNAs reduced LRP/LR expression and inhibited the accumulation of PrP(Sc) in these cells. The treatments also reduced PrP(c) levels. The anti-LRP/LR antibody, W3, abolished PrP(Sc) accumulation and reduced PrP(c) levels after seven days of incubation. Cells remained free of PrP(Sc) after being cultured for 14 additional days without the antibody, whereas the PrP(c) level was restored. Our results demonstrate the necessity of the laminin receptor (LRP/LR) for PrP(Sc) propagation in cultured cells and suggest that LRP/LR-specific antibodies could be used as powerful therapeutic tools in the treatment of transmissible spongiform encephalopathies.