Contact sensitizer nickel sulfate activates the transcription factors NF-kB and AP-1 and increases the expression of nitric oxide synthase in a skin dendritic cell line

Nuclear factor kappa B (NF-kB) and activating protein-1 (AP-1) transcription factors are ubiquitously expressed signaling molecules known to regulate the transcription of a large number of genes involved in immune responses, namely the inducible isoform of nitric oxide synthase (iNOS). In this study, we demonstrate that a fetal skin-derived dendritic cell line (FSDC) produces nitric oxide (NO) in response to the contact sensitizer nickel sulfate (NiSO(4)) and increases the expression of the iNOS protein, as determined by immunofluorescence and Western blot analysis. The sensitizer NiSO(4) increased cytoplasmic iNOS expression by 31.9 +/- 10.3% and nitrite production, as assayed by the Griess reaction, by 27.6 +/- 9.5%. Electrophoretic mobility shift assay (EMSA), showed that 30 min of FSDC exposure to NiSO(4) activates the transcription factor NF-kB by 58.2 +/- 7.0% and 2 h of FSDC exposure to NiSO(4) activates the transcription factor AP-1 by 26.0 +/- 1.4%. Together, these results indicate that NiSO(4) activates the NF-kB and AP-1 pathways and induces iNOS expression in skin dendritic cells

Involvement of JAK2 and MAPK on type II nitric oxide synthase expression in skin-derived dendritic cells

In this report, we demonstrate that a fetal mouse skin-derived dendritic cell line produces nitric oxide (NO) in response to the endotoxin [lipopolysaccharide (LPS)] and to cytokines [tumor necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF)]. Expression of the inducible isoform of NO synthase (iNOS) was confirmed by immunofluorescence with an antibody against iNOS. The tyrosine kinase inhibitor genistein decreased LPS- and GM-CSF-induced nitrite (NO(-2)) production. The effect of LPS and cytokines on NO(-2) production was inhibited by the Janus kinase 2 (JAK2) inhibitor tyrphostin B42. The p38 mitogen-activated protein kinase (p38 MAPK) inhibitor SB-203580 also reduced the NO(-2) production evoked by LPS, TNF-alpha, or GM-CSF, but it was not as effective as tyrphostin B42. Inhibition of MAPK kinase with PD-098059 also slightly reduced the effect of TNF-alpha or GM-CSF on NO(-2) production. Immunocytochemistry studies revealed that the transcription factor nuclear factor-kappaB was translocated from the cytoplasm into the nuclei of fetal skin-derived dendritic cells (FSDC) stimulated with LPS, and this translocation was inhibited by tyrphostin B42. Our results show that JAK2 plays a major role in the induction of iNOS in FSDC

Kikuchi´s disease of the xanthomathous type with cutaneous manifestation

Kikuchi's disease is a benign, self-limiting disease, whose pathogenesis remains unknown. Patients most often present with cervical lymphadenopathy, sometimes associated with fever and leukopenia. It has been reported that up to 40% of patients with Kikuchi's disease have also cutaneous eruptions, but no specific skin changes have been described. Kikuchi's disease can be subclassified into three histologic subtypes: a proliferative type, a necrotizing type and a xantomathous type. Most patients with Kikuchi's disease require no specific treatment, because the disease regresses spontaneously, within a few weeks to months. We report a case of a 31-year-old woman with xanthomatous type of Kikuchi's disease, whose first manifestation was the onset of erythematous papules with central suppuration on her face and on her left hand

Differential activation of nuclear factor kappa B subunits in a skin dendritic cell line in response to the strong sensitizer 2,4-dinitrofluorobenzene

Dendritic cell (DC) maturation is essential for the initiation of T-dependent immune responses. Nuclear factor kappa B (NF-kappaB) transcription factors are ubiquitously expressed signalling molecules, known to regulate the transcription of a large number of genes involved in immune responses, including cytokines and cell surface molecules. In this work, we studied the time-dependent activation of five members of the NF-kappaB family, p50, p52, p65, RelB and cRel, in a mouse skin DC line in response to stimulation with the strong sensitizer, 2,4-dinitrofluorobenzene (DNFB). Western blot assay revealed that exposure of fetal skin DC (FSDC) to DNFB induced the degradation of the inhibitor of NF-kappaB (IkappaB). Three out of its five members, i.e. p50, p52, and RelB, were similarly activated upon DNFB stimulation, with subsequent translocation of these subunits from the cytosol to the nucleus, but with different kinetics. In contrast, p65 expression was diminished in both the nucleus and the cytosol. The electrophoretic mobility shift assay (EMSA) showed that exposure of FSDC to DNFB induced DNA binding to NF-kappaB. Together, these results show that DNFB differentially activates the various members of the NF-kappaB family in skin DC

Value of SPET/CT image fusion in the assessment of neuroendocrine tumours with 111In-pentetreotide scintigraphy

OBJECTIVE: The purpose of this study was to evaluate the impact and clinical value of anatomical-functional image fusion in the study interpretation and clinical management of patients with neuroendocrine tumours (NET) using somatostatin receptor scintigraphy (SRS) and combined transmission and emission tomography -- single-photon emission tomography/CT (SPET/CT). MATERIAL AND METHODS: Twelve patients (8 female and 4 male; age range 32-74 y, mean 56 y) with proven or clinically suspected NET were studied with routine planar SRS and SPET/CT at 2 and 24 hours after injection of 111-222 MBq 111In-Pentetreotide. Seven patients came for staging/follow-up and 5 patients for primary tumour localization with staging. Analysis of fused images (SPET/CT) was done on a patient basis, with separated evaluation of SPET, low-dose CT images and fusion images. The gold standard for presence or absence of malignancy was pathology or clinical and imaging follow-up data. RESULTS: SRS was negative in 6 patients and positive in 6. SPET/CT provided no additional information in 6 patients, including all 6 negative studies. SPET/CT improved localization of SPET detected lesions in 6 positive studies. It defined the extent of the disease and showed bone involvement in 3 of the 6 positive studies. SPET/CT affected the diagnostic interpretation in 6 patients (50 %) and induced changes of management in 3 (25 %). CONCLUSION: The results of this study indicate that combined anatomical-functional imaging with SPET/CT significantly improves tumour localization and characterization, contributing to a better therapeutic management of patients with NET

Granulocyte-macrophage colony-stimulating factor activates the transcription of nuclear factor kappa B and induces the expression of nitric oxide synthase in a skin dendritic cell line.

Nitric oxide (NO) produced by skin dendritic cells and keratinocytes plays an important role in skin physiology, growth and remodelling. Nitric oxide is also involved in skin inflammatory processes and in modulating antigen presentation (either enhancing or suppressing it). In this study, we found that GM-CSF stimulates the expression of the inducible isoform of nitric oxide synthase (iNOS) in a fetal-skin-derived dendritic cell line (FSDC) and, consequently, increases the nitrite production from 11.9 +/- 3.2 micromol/L (basal level) to 26.9 +/- 4.2 micromol/L. Pyrrolidinedithiocarbamate (PDTC) inhibits nitrite production, with a half maximal inhibitory concentration (IC50) of 19.3 micromol/L and the iNOS protein expression in FSDC. In addition, western blot assays revealed that exposure of FSDC to GM-CSF induces the phosphorylation and degradation of the inhibitor of NF-kappaB (IkB), with subsequent translocation of the p50, p52 and RelB subunits of the transcription nuclear factor kappa B (NF-kappaB) from the cytosol to the nucleus. Electrophoretic mobility shift assays (EMSA) showed that FSDC exposure to GM-CSF activates the transcription factor NF-kappaB. Together, these results show that GM-CSF induces iNOS expression in skin dendritic cells by a mechanism involving activation of the NF-kappaB pathway

Botulinum toxin type A versus botulinum toxin type B for cervical dystonia

BACKGROUND: This is an update of a Cochrane review first published in 2003. Cervical dystonia is the most common form of focal dystonia and is a disabling disorder characterised by painful involuntary head posturing. There are two available formulations of botulinum toxin, with botulinum toxin type A (BtA) usually considered the first line therapy for this condition. Botulinum toxin type B (BtB) is an alternative option, with no compelling theoretical reason why it might not be as- or even more effective - than BtA. OBJECTIVES: To compare the efficacy, safety and tolerability of botulinum toxin type A (BtA) versus botulinum toxin type B (BtB) in people with cervical dystonia. SEARCH METHODS: To identify studies for this review we searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were last run in October 2016. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) comparing BtA versus BtB in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two independent authors assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third author. We performed meta-analyses using the random-effects model, for the comparison BtA versus BtB to estimate pooled effects and corresponding 95% confidence intervals (95% CI). No prespecified subgroup analyses were carried out. The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. MAIN RESULTS: We included three RCTs, all new to this update, of very low to low methodological quality, with a total of 270 participants.Two studies exclusively enrolled participants with a known positive response to BtA treatment. This raises concerns of population enrichment, with a higher probability of benefit from BtA treatment. None of the trials were free of for-profit bias, nor did they provide information regarding registered study protocols. All trials evaluated the effect of a single Bt treatment session, and not repeated treatment sessions, using doses from 100 U to 250 U of BtA (all onabotulinumtoxinA, or Botox, formulations) and 5000 U to 10,000 U of BtB (rimabotulinumtoxinB, or Myobloc/Neurobloc).We found no difference between the two types of botulinum toxin in terms of overall efficacy, with a mean difference of -1.44 (95% CI -3.58 to 0.70) points lower on the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) for BtB-treated participants, measured at two to four weeks after injection. The proportion of participants with adverse events was also not different between BtA and BtB (BtB versus BtA risk ratio (RR) 1.40; 95% CI 1.00 to 1.96). However, when compared to BtA, treatment with BtB was associated with an increased risk of one adverse events of special interest, namely treatment-related sore throat/dry mouth (BtB versus BtA RR of 4.39; 95% CI 2.43 to 7.91). Treatment-related dysphagia (swallowing difficulties) was not different between BtA and BtB (RR 2.89; 95% CI 0.80 to 10.41). The two types of botulinum toxin were otherwise clinically non-distinguishable in all the remaining outcomes. AUTHORS' CONCLUSIONS: The previous version of this review did not include any trials, since these were still ongoing at the time. Therefore, with this update we are able to change the conclusions of this review. There is low quality evidence that a single treatment session of BtA (specifically onabotulinumtoxinA) and a single treatment session of BtB (rimabotulinumtoxinB) are equally effective and safe in the treatment of adults with certain types of cervical dystonia. Treatment with BtB appears to present an increased risk of sore throat/dry mouth, compared to BtA. Overall, there is no clinical evidence from these single-treatment trials to support or contest the preferential use of one form of botulinum toxin over the other

Botulinum toxin type B for cervical dystonia

BACKGROUND: This is an update of a Cochrane review first published in 2004, and previously updated in 2009 (no change in conclusions). Cervical dystonia is a frequent and disabling disorder characterised by painful involuntary head posturing. Botulinum toxin type A (BtA) is usually considered the first line therapy for this condition, although botulinum toxin type B (BtB) is an alternative option. OBJECTIVES: To compare the efficacy, safety and tolerability of botulinum toxin type B (BtB) versus placebo in people with cervical dystonia. SEARCH METHODS: We identified studies for inclusion in the review using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists of articles and conference proceedings, last run in October 2015. We ran the search from 1977 to 2015. The search was unrestricted by language. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtB versus placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two independent authors assessed records, selected included studies, extracted data using a paper pro forma and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third author. We performed one meta-analysis for the comparison BtB versus placebo. We used random-effects models when there was heterogeneity and fixed-effect models when there was no heterogeneity. In addition, we performed pre-specified subgroup analyses according to BtB doses and BtA previous clinical responsiveness. The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. The primary safety outcome was the number of participants with any adverse event. MAIN RESULTS: We included four RCTs of moderate overall methodological quality, including 441 participants with cervical dystonia. Three studies excluded participants known to have poorer response to Bt treatment, therefore including an enriched population with a higher probability of benefiting from Bt treatment. None of the trials were independently funded. All RCTs evaluated the effect of a single Bt treatment session using doses between 2500 U and 10,000 U. BtB was associated with an improvement of 14.7% (95% CI 9.8% to 19.5) in the patients' baseline clinical status as assessed by investigators, with reduction of 6.8 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-total score) at week 4 after injection (95% CI 4.54 to 9.01). Mean difference (MD) in TWSTRS-pain score at week 4 was 2.20 (95% CI 1.25 to 3.15). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups in the withdrawals rate due to adverse events or in the proportion of participants with adverse events. However, BtB-treated patients had a 7.65 (95% CI 2.75 to 21.32) and a 6.78 (95% CI 2.42 to 19.05) increased risk of treatment-related dry mouth and dysphagia, respectively. Statistical heterogeneity between studies was low to moderate for most outcomes. All tested dosages were efficacious against placebo without clear-cut evidence of a dose-response gradient. However, duration of effect (time until return to baseline TWSTRS-total score) and risk of dry mouth and dysphagia were greater in the subgroup of participants treated with higher BtB doses. Subgroup analysis showed a higher improvement with BtB among BtA-non-responsive participants, although there were no differences in the effect size between the BtA-responsive and non-responsive subgroups. AUTHORS' CONCLUSIONS: A single BtB-treatment session is associated with a significant and clinically relevant reduction of cervical dystonia impairment including severity, disability and pain, and is well tolerated, when compared with placebo. However, BtB-treated patients are at an increased risk of dry mouth and dysphagia. There are no data from RCTs evaluating the effectiveness and safety of repeated BtB injection cycles. There are no RCT data to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, and impact on quality of life

Botulinum toxin type A therapy for cervical dystonia

BACKGROUND: This is an update of a Cochrane Review first published in 2005. Cervical dystonia is the most common form of focal dystonia, and is a highly disabling movement disorder, characterised by involuntary, usually painful, head posturing. Currently, botulinum toxin type A (BtA) is considered the first line therapy for this condition. OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo, in people with cervical dystonia. SEARCH METHODS: We searched Cochrane Movement Disorders' Trials Register, CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. All elements of the search, with no language restrictions, were last run in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third review author. We performed meta-analyses using a random-effects model, for the comparison of BtA versus placebo, to estimate pooled effects and corresponding 95% confidence intervals (95% CI). We performed preplanned subgroup analyses according to BtA dose used, the BtA formulation used, and the use (or not) of guidance for BtA injections. The primary efficacy outcome was improvement in cervical dystonia-specific impairment. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We included nine RCTs, with moderate, overall risk of bias, that included 1144 participants with cervical dystonia. Seven studies excluded participants with poorer responses to BtA treatment, therefore, including an enriched population with a higher probability of benefiting from this therapy. Only one trial was independently funded. All RCTs evaluated the effect of a single BtA treatment session, using doses from 150 U to 500 U of onabotulinumtoxinA (Botox), 120 U to 240 U of incobotulinumtoxinA (Xeomin), and 250 U to 1000 U of abobotulinumtoxinA (Dysport). BtA resulted in a moderate to large improvement from the participant's baseline clinical status, assessed by the investigators, with a mean reduction of 8.09 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS total score) at week four after injection (95% CI 6.22 to 9.96; I² = 0%) compared to placebo. This corresponded, on average, to a 18.4% improvement from baseline. The mean difference (MD) in TWSTRS pain subscore at week four was 2.11 (95% CI 1.38 to 2.83; I² = 0%) compared to placebo. Overall, both participants and clinicians reported an improvement of subjective clinical status. It was unclear if dropouts due to adverse events differed (risk ratio (RR) 2.51; 95% CI 0.42 to 14.94; I² = 0%) However, BtA treatment increased the risk of experiencing an adverse event (R) 1.23; 95% CI 1.05 to 1.43; I² = 28%). Neck weakness (14%; RR 3.40; 95% CI 1.19 to 9.71; I² = 15%), dysphagia (11%; RR 3.19; 95% CI 1.79 to 5.70; I² = 0%), and diffuse weakness or tiredness (8%; RR 1.80; 95% CI 1.10 to 2.95; I² = 0%) were the most common treatment-related adverse events. Treatment with BtA resulted in a decreased risk of dropouts. We have moderate certainty in the evidence across all of the aforementioned outcomes, with the exception of subjective assessment and tolerability, in which we have high confidence in the evidence. We found no evidence supporting the existence of a clear dose-response relationship between BtA and improvement in cervical dystonia-specific impairment, a destinction between BtA formulations, or a variation with use of EMG-guided injection for efficacy outcomes. Due to clinical heterogeneity, we did not pool health-related quality of life data, duration of clinical effect, or the development of secondary non-responsiveness. AUTHORS' CONCLUSIONS: We are moderately certain in the evidence that a single BtA treatment session resulted in a clinically relevant reduction of cervical dystonia-specific impairment, and pain, and highly certain that it is well tolerated, compared with placebo. There is moderate-certainty evidence that people treated with BtA are at an increased risk of developing adverse events, most notably, dysphagia, neckweakness and diffuse weakness or tiredness. There are no data from RCTs evaluating the effectiveness and safety of repeated BtA injection cycles. There is no evidence from RCTs to allow us to draw definitive conclusions on the optimal treatment intervals and doses, the usefulness of guidance techniques for injection, the impact on quality of life, or the duration of treatment effect

Botulinum toxin type A therapy for hemifacial spasm

BACKGROUND: This is an update of a Cochrane Review, first published in 2005. Hemifacial spasm (HFS) is characterised by unilateral, involuntary contractions of the muscles innervated by the facial nerve. It is a chronic disorder, and spontaneous recovery is very rare. The two treatments routinely available are microvascular decompression and intramuscular injections with botulinum toxin type A (BtA). OBJECTIVES: To compare the efficacy, safety, and tolerability of BtA versus placebo in people with HFS. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, reference lists of articles, and conference proceedings in July 2020. We ran the electronic database search, with no language restrictions, in July 2020. SELECTION CRITERIA: Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtA versus placebo in adults with HFS. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed records. We planned to select included studies, extract data using a paper pro forma, and evaluate the risk of bias. We resolved disagreements by consensus, or by consulting a third review author. We planned to perform meta-analyses. The primary efficacy outcome was HFS-specific improvement. The primary safety outcome was the proportion of participants with any adverse event. MAIN RESULTS: We found no parallel-group randomised controlled trials comparing BtA and placebo in HFS. AUTHORS' CONCLUSIONS: We did not find any randomised trials that evaluated the efficacy and safety of botulinum toxin type A in people with hemifacial spasm, so we are unable to draw any conclusions. Observational data show a strong association between BtA treatment and symptom improvement, and a favourable safety profile. While it is unlikely that future placebo-controlled RCTs will evaluate absolute efficacy and safety, they should address relevant questions for both people with HFS (such as long-term effects, quality of life, and other patient-reported outcomes), and clinicians (such as relative effectiveness of different BtA formulations and schemes of treatment) to better guide clinical practice.)