ABSTRACT
It has recently been revealed that mutation of the IL36RN gene contributes to the development of generalized pustular psoriasis (GPP). The IL36RN gene encodes interleukin (IL)-36 receptor antagonist (IL-36Ra), which has antagonistic roles against IL-36α, -36ß, and -36γ. Previously, sanger sequencing performed in 62 Chinese GPP patients to identify IL36RN mutations revealed a new variant, c.245C>T (p.Pro82Leu), in a single heterozygous state in a patient with adult-onset GPP with psoriasis vulgaris. Since this p.Pro82Leu variant was not found in the psoriasis vulgaris or control groups in their study, they speculated that this variant might lead to exacerbated inflammatory responses. Meanwhile, Sorting Intolerant From Tolerant and PolyPhen-2, pathogenicity prediction tools, predict this variant as tolerated and benign. To date, its pathogenicity is unknown. We experienced a patient with GPP harboring the p.Pro82Leu variant, and investigated mRNA and protein expressions of IL-36Ra. Polymerase chain reaction conducted on hair follicle samples obtained from the scalp of the patient with GPP harboring the p.Pro82Leu using primers to detect mRNA of exons 2 and 5 in IL36RN demonstrated mRNA expression of IL36RN. Immunohistochemical staining revealed IL-36Ra expression in the keratinocytes of the patient with GPP harboring the p.Pro82Leu as in those of a GPP patient without the mutation (positive control). Furthermore, quantitative analysis of the immunofluorescent staining by ImageJ revealed that the expression level of IL-36Ra in the keratinocytes of the patient with GPP harboring p.Pro82Leu was higher than that in the healthy control and not lower than that in the GPP patients without the mutation. Our results indicate no aberrant splicing in this variant. In addition, according to the 1000 Genomes Project, this variant could be a founder mutation. Considering these factors together, this variant is unlikely to be associated with the development of GPP.
Subject(s)
Interleukins , Psoriasis , Adult , Humans , Interleukins/genetics , Interleukins/metabolism , Psoriasis/genetics , Mutation , Polymerase Chain Reaction , Acute Disease , Chronic Disease , RNA, MessengerABSTRACT
Psoriasis is characterized by increased dermal vascularity, indicating that aberrant angiogenesis is associated with the pathogenesis of psoriasis. Data on angiogenesis-related factors in psoriasis patients are limited. We explored serum levels of angiogenesis-related factors in patients with psoriasis, and investigated their association with clinical severity and laboratory data. Psoriasis patients visiting our hospital from April 2013 to April 2018 and healthy controls were included in this study. Serum levels of angiopoietin-1, fibroblast growth factor (FGF)-basic, epidermal growth factor (EGF), platelet endothelial cell adhesion molecule (PECAM)-1, placental growth factor, and vascular endothelial growth factor (VEGF) were measured by LEGENDplex. Serum samples obtained from 10 healthy controls, 18 patients with psoriasis vulgaris (PsV), 24 patients with psoriatic arthritis (PsA), and 13 patients with generalized pustular psoriasis (GPP) were analyzed. The serum angiopoietin-1 level was elevated in the PsV, PsA, and GPP patients. GPP patients had a higher serum VEGF level than healthy controls. In contrast, serum levels of EGF and PECAM-1 were lower in the PsV, PsA, and GPP patients than in healthy controls. The serum FGF-basic level was lower in the PsA and GPP patients than in healthy controls. Serum levels of FGF-basic in PsA and GPP patients, PECAM-1 in PsA patients, and VEGF in GPP patients became closer to the respective levels in healthy controls after systemic therapy. The serum FGF-basic level was positively correlated with the psoriasis area and severity index and the number of circulating eosinophils in GPP patients. The serum VEGF level was correlated positively with the serum C-reactive protein (CRP) level and erythrocyte sedimentation rate, and negatively with the serum albumin level in GPP patients. In conclusion, our exploratory study revealed that psoriasis affects serum levels of certain angiogenesis-related factors. Some of these factors could be biomarkers of treatment outcomes, clinical severity, and systemic inflammation.
Subject(s)
Arthritis, Psoriatic , Psoriasis , Humans , Female , Vascular Endothelial Growth Factor A , Angiopoietin-1 , Epidermal Growth Factor , Platelet Endothelial Cell Adhesion Molecule-1 , Placenta Growth Factor , Psoriasis/pathologyABSTRACT
BACKGROUND: Apremilast, a selective inhibitor of the enzyme phosphodiesterase 4, is efficacious for psoriasis. However, detailed in vivo effects of apremilast on psoriasis remain to be elucidated. OBJECTIVE: To examine the in vivo effects of apremilast on psoriasis. METHODS: Psoriasiform dermatitis was induced by applying imiquimod (IMQ) on the murine shaved back skin for six days. Mice were treated with apremilast or vehicle intraperitoneally daily. RESULTS: Apremilast alleviated IMQ-induced psoriasiform dermatitis clinically and pathologically on days 3-6 by reducing infiltration of antigen-presenting cells and interleukin (IL)-17A-positive cells and increasing infiltration of Foxp3-postive cells into the skin on day 6, although a significant increase in IL-10 mRNA level was not observed on day 2. In addition, mRNA expression of IL-17A, IL-17F, and IL-22 was lower in the skin of IMQ-applied mice treated with apremilast than in those without apremilast on day 2, and apremilast inhibited infiltration of IL-17A-producing γδ T cells into the dermis on day 6. Furthermore, apremilast induced regulatory T cells and regulatory B cells in the spleen but not in the draining lymph nodes. CONCLUSION: Apremilast downregulated IL-17 production and induced splenic regulatory B cells and regulatory T cells in an IMQ-induced psoriasiform dermatitis mouse model.
Subject(s)
B-Lymphocytes, Regulatory/immunology , Interleukin-17/antagonists & inhibitors , Psoriasis/drug therapy , T-Lymphocytes, Regulatory/immunology , Thalidomide/analogs & derivatives , Animals , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/immunology , Female , Humans , Imiquimod/administration & dosage , Imiquimod/toxicity , Interleukin-17/metabolism , Mice , Psoriasis/chemically induced , Psoriasis/immunology , Psoriasis/pathology , Spleen/cytology , Spleen/drug effects , Spleen/immunology , Spleen/pathology , Thalidomide/pharmacology , Thalidomide/therapeutic useABSTRACT
BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Interleukin (IL)-17A plays a key role in the pathogenesis of psoriasis. Fingolimod, which is available for the treatment of multiple sclerosis, exerts anti-inflammatory effects by sequestrating inflammatory lymphocytes in secondary lymphoid tissues and the thymus. The effect of fingolimod on psoriasis has not been reported yet. OBJECTIVE: Our objectives were to investigate the effect of fingolimod on psoriasis utilizing mice with imiquimod (IMQ)-induced psoriasiform dermatitis, and explore the possibility of fingolimod as a therapeutic agent for psoriasis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Fingolimod prepared in phosphate-buffered saline (PBS), or PBS alone as a control, was administered intraperitoneally daily from days 0 to 5. RESULTS: Fingolimod ameliorated IMQ-induced psoriasis dermatitis clinically and histologically. On day 6, the mRNA expression level of IL-17A was lower in the skin of fingolimod-treated mice than in that of PBS-treated mice, whereas it was higher in the inguinal lymph nodes of fingolimod-treated mice than in those of PBS-treated mice. Flow cytometric analyses revealed that fingolimod reduced IL-17A-producing ?d T cells infiltrating into the skin, whereas it increased these cells in the inguinal lymph nodes. Fingolimod inhibited egress of Langerhans cells from the skin to lymph nodes. CONCLUSION: Our results demonstrated that fingolimod showed effectiveness for IMQ-induced psoriasiform dermatitis by hindering the emigration of IL-17A-producing ?d T cells from the lymph nodes to the skin, and suggest that fingolimod is a promising candidate for the treatment of psoriasis.
Subject(s)
Fingolimod Hydrochloride/pharmacology , Intraepithelial Lymphocytes/drug effects , Lymph Nodes/drug effects , Psoriasis/drug therapy , Skin/drug effects , Animals , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/immunology , Drug Evaluation, Preclinical , Female , Fingolimod Hydrochloride/therapeutic use , Humans , Imiquimod/administration & dosage , Imiquimod/immunology , Interleukin-17/metabolism , Intraepithelial Lymphocytes/immunology , Intraepithelial Lymphocytes/metabolism , Langerhans Cells/immunology , Langerhans Cells/metabolism , Lymph Nodes/cytology , Lymph Nodes/immunology , Lymph Nodes/metabolism , Mice , Psoriasis/immunology , Psoriasis/pathology , Skin/cytology , Skin/immunology , Skin/metabolism , Up-Regulation/drug effects , Up-Regulation/immunologySubject(s)
Adipokines/genetics , Psoriasis/genetics , RNA, Messenger/metabolism , Subcutaneous Fat/pathology , Up-Regulation/immunology , Adipokines/immunology , Adult , Aged , Female , Gene Expression Profiling , Humans , Male , Middle Aged , Psoriasis/immunology , Psoriasis/pathology , RNA, Messenger/analysis , Skin/immunology , Skin/pathology , Subcutaneous Fat/immunologyABSTRACT
Thymus and activation-regulated chemokine (TARC) is designated as a T-helper 2-type chemokine and its expression is upregulated in patients with atopic dermatitis. Previous studies reported that serum TARC levels in patients with psoriasis vulgaris (PsV) were comparable with those in healthy controls. However, the association of clinical severity of psoriasis with serum TARC levels and serum TARC levels in patients with psoriatic arthritis (PsA) or generalized pustular psoriasis (GPP) have never been reported. We investigated the association of serum TARC level with psoriasis by the type of psoriasis, and examine correlations of serum TARC levels with clinical severity scores and other results of blood tests. Data on 75 patients (51 men and 24 women; PsV, 30 patients; PsA, 29 patients; GPP, 16 patients) were analyzed. The serum TARC level was significantly higher in patients with GPP than in patients with PsV and patients with PsA. There was a positive correlation between serum TARC level and Psoriasis Area and Severity Index score (r = 0.3499, P = 0.0030). The serum TARC levels decreased after treatment in GPP patients. Our study revealed that the serum TARC level can potentially be one of the biomarkers reflecting the severity or systemic inflammation caused by psoriasis in patients with psoriasis, although not as much as in patients with atopic dermatitis. Furthermore, serum TARC levels were high in patients with GPP. Those were decreased by treatment, suggesting that serum TARC levels could be utilized as an objective biomarker to evaluate a therapeutic effect in individual GPP patients. Further accumulation of cases and further research are needed to elucidate the role of TARC in psoriasis.
Subject(s)
Chemokine CCL17 , Dermatitis, Atopic , Eczema , Psoriasis , Female , Humans , Male , Severity of Illness IndexABSTRACT
Mal de Meleda (MDM) is a rare, autosomal recessive form of palmoplantar keratoderma due to mutations in the gene, encoding for secreted lymphocyte antigen 6/urokinase-type plasminogen activator receptor related protein 1 (SLURP1). We report a four-year-old Taiwanese MDM female case whose biopsy specimen of hyperkeratotic lesions showed abnormal keratinization and cutaneous inflammation with characteristic transmission electron microscopic (TEM) findings and immunostaining results. The patient presented with pruritic and severely hyperkeratotic plaques on the bilateral palms and soles whichwere fringed with erythematous scaly areas. A homozygous c.256 G>A mutation, predicting a conversion of p.Gly86Arg, in SLURP1gene was detected. Histopathological examinations showed marked hyperkeratosis, acanthosis and hypergranulosis in the epidermis, accompanied by perivascular lymphocytic infiltrates in the dermis. The whole layers of the epidermis and perivascular infiltrates of the dermis were stained positive with anti-tumor necrosis factor alpha (TNFα) antibody in the biopsy specimen from the sole and the ankle. TEM examination of the biopsy specimen from the plantar hyperkeratotic plaque showed various-sized vacuoles surrounding nuclei of many keratinocytes in the spinous layer. In addition, there were numerous irregular keratohyaline granules in the granular layer. Several microorganisms and many lipid-like droplets were found in the thickened cornified layer. SLURP1 protein is known as a marker of late differentiation, predominantly expressed in the granular layer, and also known to have an inhibitory effect on TNFα release. Our results exhibited excessive TNFα expression in keratinocytes and perivascular infiltrates of the dermis, and several characteristic morphological observations of keratinocytes in MDM.
Subject(s)
Antigens, Ly/genetics , Keratinocytes/pathology , Keratoderma, Palmoplantar/diagnosis , Skin/immunology , Urokinase-Type Plasminogen Activator/genetics , Biopsy , Child, Preschool , DNA Mutational Analysis , Female , Foot , Hand , Homozygote , Humans , Keratinocytes/immunology , Keratoderma, Palmoplantar/genetics , Keratoderma, Palmoplantar/immunology , Keratoderma, Palmoplantar/pathology , Microscopy, Electron, Transmission , Mutation , Pedigree , Skin/cytology , Skin/pathology , Skin/ultrastructure , Tumor Necrosis Factor-alpha/immunology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
The association of psoriasis with thyroid dysfunction has been investigated; however, it remains controversial. Some papers indicate it, and others do not. Thereby, we investigated the prevalence of thyroid dysfunction in patients with psoriasis vulgaris (PsV), psoriatic arthritis (PsA) and generalized pustular psoriasis (GPP), and the relationship between the severity of psoriasis with serum free triiodothyronine (fT3), free thyroxine (fT4) and thyroid-stimulating hormone levels. Data on 85 psoriatic patients visiting our hospital from January 2015 to November 2017 (54 men and 31 women; 51 PsV, 23 PsA 23 and 11 GPP) were retrospectively analyzed. Fourteen percent of psoriatic patients had thyroid dysfunction. The percentage of patients with thyroid dysfunction was the highest in those with GPP (45% GPP, 13% PsA, 8% PsV). Patients with thyroid dysfunction demonstrated significantly higher Psoriasis Area and Severity Index scores and elevated serum C-reactive protein (CRP) levels than those without thyroid dysfunction. A significant negative correlation was observed between the serum levels of CRP and fT3 (P = 0.0032, r = -0.4635). Our data indicate that thyroid dysfunction in patients with psoriasis is associated with inflammation caused by psoriasis.
Subject(s)
Psoriasis/complications , Thyroid Diseases/epidemiology , Thyroid Gland/immunology , Adult , Aged , C-Reactive Protein/analysis , C-Reactive Protein/immunology , Female , Humans , Male , Middle Aged , Prevalence , Psoriasis/blood , Psoriasis/diagnosis , Psoriasis/immunology , Retrospective Studies , Severity of Illness Index , Thyroid Diseases/blood , Thyroid Diseases/diagnosis , Thyroid Diseases/immunology , Thyroid Gland/metabolism , Thyrotropin/blood , Thyrotropin/metabolism , Thyroxine/blood , Thyroxine/metabolism , Triiodothyronine/blood , Triiodothyronine/metabolismABSTRACT
Psoriasis is a T-helper (Th)1/Th17-mediated, chronic inflammatory dermatitis that is commonly treated with topical corticosteroids and vitamin D3 analogs. The combination of a topical corticosteroid and vitamin D3 analog showed superior efficacy to each alone in clinical trials; however, the mechanisms by which the topical corticosteroid and vitamin D3 analog exert their effects on lesional skin in combination and each alone remain unknown. In this study, we examined the effects of combined calcipotriol (Cal)/betamethasone dipropionate (BD) ointment on psoriasis in vivo, utilizing imiquimod (IMQ)-induced murine psoriasiform skin inflammation, compared with each alone. Vehicle, Cal/BD, Cal or BD was applied on the shaved back skin for 3 consecutive days. Then, IMQ was applied for 6 consecutive days. Twenty-four hours after the last IMQ treatment, the murine skin was evaluated clinically and pathologically. mRNA expressions were examined by quantitative polymerase chain reaction. All ointments alleviated IMQ-induced psoriasiform skin inflammation clinically in comparison with vehicle application. Cal/BD suppressed mRNA expressions of cytokines involved in psoriasis pathogenesis such as interleukin (IL)-17A and IL-22 efficiently. Cal alone induced IL-10 expression, whereas BD alone reduced IL-6 mRNA expression and the number of phosphorylated signal transducer and activator of transcription 3-positive cells in lesional skin. Our study revealed that Cal and BD have different effects on IMQ-induced psoriasiform skin. Some of the immune effects of Cal and BD may be additive or synergistic, which may account for the superior clinical efficacy of their combination.
Subject(s)
Betamethasone/analogs & derivatives , Calcitriol/analogs & derivatives , Dermatologic Agents/pharmacology , Glucocorticoids/physiology , Psoriasis/drug therapy , Administration, Cutaneous , Animals , Betamethasone/pharmacology , Betamethasone/therapeutic use , Calcitriol/pharmacology , Calcitriol/therapeutic use , Cytokines/metabolism , Dermatologic Agents/therapeutic use , Disease Models, Animal , Drug Synergism , Drug Therapy, Combination/methods , Female , Gene Expression Regulation/drug effects , Gene Expression Regulation/immunology , Glucocorticoids/therapeutic use , Humans , Imiquimod/toxicity , Mice , Ointments , Psoriasis/blood , Psoriasis/immunology , Psoriasis/pathology , Skin/drug effects , Skin/immunology , Skin/pathology , Th1 Cells/drug effects , Th1 Cells/immunology , Th1 Cells/metabolism , Th17 Cells/drug effects , Th17 Cells/immunology , Th17 Cells/metabolismABSTRACT
BACKGROUND: Psoriasis is a chronic inflammatory skin disease. Anti-TNFα, IL-17A and IL-23p19 antibodies are effective for psoriasis. However, the contribution of regulatory T cells (Treg) in their effectiveness remains to be elucidated. OBJECTIVE: We investigated the effects of TNFα, IL-17A and IL-23p19 inhibition on Tregs in imiquimod-induced psoriasiform dermatitis. METHODS: Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Mice were treated with anti-TNFα, IL-17A or IL-23p19 monoclonal antibodies every other day from one day before imiquimod application. RESULTS: Administration of anti-TNFα, IL-17A or IL-23p19 antibodies improved the clinical score and downregulated Th17-related cytokines and chemokines, while IL-23p19 antibodies upregulated IL-10 mRNA expression. Anti-IL-17A or IL-23p19 antibody-treated imiquimod-applied mice showed a significant increase in the number of Foxp3+ IL-10+ Tregs. Recipient mice adoptively transferred with Tregs derived from donor mice treated with antibodies demonstrated clinical and pathological improvement in imiquimod-induced psoriasiform dermatitis. Anti-IL-17A or IL-23p19 antibody-induced Tregs significantly increased the number of Foxp3+ cells and IL-10 expression in imiquimod-induced psoriasiform dermatitis in recipient mice but anti-TNFα antibody-induced Tregs did not. CONCLUSION: Anti-IL-17A or IL-23p19 antibody inhibits the IL-17/IL-23 signaling pathway, and induces expansion of Tregs and their suppressive capacity in imiquimod-induced psoriasiform dermatitis.
Subject(s)
Antibodies, Monoclonal/pharmacology , Interleukin-17/antagonists & inhibitors , Interleukin-23 Subunit p19/antagonists & inhibitors , Psoriasis/drug therapy , T-Lymphocytes, Regulatory/drug effects , Adoptive Transfer , Animals , Antibodies, Monoclonal/therapeutic use , Disease Models, Animal , Female , Humans , Imiquimod/administration & dosage , Imiquimod/immunology , Interleukin-17/metabolism , Interleukin-23 Subunit p19/metabolism , Mice , Psoriasis/immunology , Signal Transduction/drug effects , Signal Transduction/immunology , Skin , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/transplantation , Th17 Cells/drug effects , Th17 Cells/immunology , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
BACKGROUND: Psoriasis is a Th1/Th17-mediated inflammatory dermatosis treated with topical corticosteroids and vitamin D3 analogs (VD3 As). OBJECTIVE: To compare the effects of a VD3 A maxacalcitol and betamethasone valerate (BV) steroid lotion on topical imiquimod (IMQ)-induced psoriasiform skin inflammation. METHODS: Female BALB/c mice were treated with vehicle, maxacalcitol or BV lotion on the skin for 3 days, and IMQ cream for 6 days. q-PCR, H&E, immunohistochemistry and immunofluorescence studies were performed on skin samples. Additionally, mice were treated with vehicle, maxacalcitol or BV lotion for 3 days and CD4+CD25+ regulatory T cells (Tregs) and CD4+CD25- cells from each group were isolated from lymph nodes. Adoptive transfer of the cells was performed on recipient mice which were treated with IMQ cream for 6 days, and skin samples were obtained for q-PCR and H&E staining. RESULTS: Maxacalcitol and BV were comparable in regards clinical improvement, although maxacalcitol reduced the MHC Class II+ inflammatory cell infiltration more than BV in IMQ skin. While both treatments downregulated IL-17 A, IL-17 F, IL-22, IL-12p40, TNF-α and IL-6 mRNA expression levels, only maxacalcitol downregulated IL-23p19 expression. Significantly increased Foxp3+ cell infiltrations and IL-10 expression were noted in maxacalcitol-treated IMQ skin. Adoptive transfer of Treg cells from maxacalcitol-treated donor mice improved IMQ-induced inflammation clinically and histopathologically more than the recipients of Treg cells from BV-treated donor groups, showing reduced levels of inflammatory cytokines and increased IL-10 expression. CONCLUSION: These results indicate that maxacalcitol reduces psoriasiform skin inflammation by inducing Treg cells as well as downregulating IL-23 and IL-17 production.
Subject(s)
Calcitriol/analogs & derivatives , Dermatologic Agents/pharmacology , Interleukin-17/metabolism , Interleukin-23/metabolism , Psoriasis/drug therapy , T-Lymphocytes, Regulatory/drug effects , Adoptive Transfer , Animals , Betamethasone Valerate/pharmacology , Betamethasone Valerate/therapeutic use , Calcitriol/pharmacology , Calcitriol/therapeutic use , Dermatologic Agents/therapeutic use , Down-Regulation , Female , Humans , Imiquimod/immunology , Interleukin-17/immunology , Interleukin-23/immunology , Mice , Mice, Inbred BALB C , Psoriasis/immunology , Psoriasis/pathology , Skin/cytology , Skin/immunology , Skin/pathology , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Treatment OutcomeABSTRACT
OBJECTIVE: To identify the gene mutation of tubular aggregate myopathy (TAM) and gain mechanistic insight into the pathogenesis of the disorder. METHODS: We described a family affected by autosomal dominant TAM and performed exome and Sanger sequencing to identify mutations. We further analyzed the functional significance of the identified mutation by expression studies and intracellular Ca(2+) measurements. RESULTS: A 42-year-old man presented with slowly progressive muscle weakness and atrophy in all 4 limbs and the trunk. Muscle biopsy and microscopic examination revealed tubular aggregates in his skeletal muscle. Genetic analysis of this family identified a novel heterozygous mutation, c.1450_1451insGA (p.Ile484ArgfsX21), in stromal interaction molecule 1 (STIM1), a Ca(2+) sensor in sarcoplasmic reticulum. We transfected cultured cells with STIM1 and demonstrated that the mutant STIM1 exhibited aggregation-like appearance in shrunk cytoplasm. Furthermore, we revealed that the intracellular Ca(2+) influx is decreased by the mutant STIM1. CONCLUSIONS: The novel mutation p.Ile484ArgfsX21 is located in the cytoplasmic C-terminal inhibitory domain (CTID) of STIM1. However, all mutations reported so far in TAM reside in the luminal N-terminal EF hand region. The aggregation-like appearance of STIM1 and the decreased intracellular Ca(2+) influx in cells transfected with CTID mutant are in sharp contrast to these previous reports. Taken together, these findings indicate that mutations of STIM1 cause TAM through the dysregulation of Ca(2+) homeostasis.
ABSTRACT
PURPOSE: Diabetic patients without symptoms of carpal tunnel syndrome (CTS) may frequently show a prolongation of their median distal latency. Previous authors have reported that diabetic polyneuropathy (DPN) and CTS were differentiated by evaluating the sensory conduction velocity (SCV) distal to the palm. This study aimed to clarify this issue. METHODS: The subjects consisted of 30 DPN patients without clinical CTS and 50 CTS patients without diabetes mellitus. An antidromic sensory conduction study stimulating the median nerve at the wrist and palm was performed. The SCV distal to the palm (SCVpf) and across the carpal tunnel (SCVwp) and the sensory nerve action potential amplitude following palmar stimulation (AMP-p) were evaluated. RESULTS: The SCVwp was significantly lower than the SCVpf in DPN patients, implying the frequent presence of subclinical lesion at the carpal tunnel. The SCVpf was similar for both groups. The AMP-p was disproportionately low in relation to SCVwp in DPN patients, as compared with CTS patients. CONCLUSIONS: The polyneuropathic feature of DPN is primarily expressed as axonal loss. The diabetic axonal loss index has been introduced, which enabled to determine the co-presence, isolated presence, or absence of DPN/CTS in the electrophysiological sense.
Subject(s)
Carpal Tunnel Syndrome/diagnosis , Diabetic Retinopathy/diagnosis , Electric Stimulation , Hand/innervation , Adolescent , Adult , Aged , Electroencephalography , Electromyography , Female , Humans , Male , Middle Aged , Neural Conduction/physiology , Reaction Time/physiology , Retrospective Studies , Statistics as Topic , Young AdultABSTRACT
Several types of muscular dystrophy are caused by defective linkage between α-dystroglycan (α-DG) and laminin. Among these, dystroglycanopathy, including Fukuyama-type congenital muscular dystrophy (FCMD), results from abnormal glycosylation of α-DG. Recent studies have shown that like-acetylglucosaminyltransferase (LARGE) strongly enhances the laminin-binding activity of α-DG. Therefore, restoration of the α-DG-laminin linkage by LARGE is considered one of the most promising possible therapies for muscular dystrophy. In this study, we generated transgenic mice that overexpress LARGE (LARGE Tg) and crossed them with dy(2J) mice and fukutin conditional knockout mice, a model for laminin α2-deficient congenital muscular dystrophy (MDC1A) and FCMD, respectively. Remarkably, in both the strains, the transgenic overexpression of LARGE resulted in an aggravation of muscular dystrophy. Using morphometric analyses, we found that the deterioration of muscle pathology was caused by suppression of muscle regeneration. Overexpression of LARGE in C2C12 cells further demonstrated defects in myotube formation. Interestingly, a decreased expression of insulin-like growth factor 1 (IGF-1) was identified in both LARGE Tg mice and LARGE-overexpressing C2C12 myotubes. Supplementing the C2C12 cells with IGF-1 restored the defective myotube formation. Taken together, our findings indicate that the overexpression of LARGE aggravates muscular dystrophy by suppressing the muscle regeneration and this adverse effect is mediated via reduced expression of IGF-1.
Subject(s)
Down-Regulation , Insulin-Like Growth Factor I/metabolism , Muscle, Skeletal/physiopathology , Muscular Dystrophy, Animal/metabolism , Muscular Dystrophy, Animal/physiopathology , N-Acetylglucosaminyltransferases/metabolism , Regeneration , Animals , Cell Fusion , Cell Line , Dystroglycans/metabolism , Glycosylation , Humans , Mice , Mice, Transgenic , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/pathology , Myoblasts/metabolism , Myoblasts/pathology , Phenotype , Proteins/metabolism , Transfection , TransferasesABSTRACT
INTRODUCTION: We describe a previously unreported pitfall, spread of the stimulus at the elbow to the radial nerve, in an antidromic sensory nerve conduction study of the lateral antebrachial cutaneous (LAC) nerve. METHODS: Subjects consisted of 80 healthy volunteers, and both sides were examined for each subject. Besides routine recording of the LAC nerve, sensory nerve action potentials (SNAPs) of the radial nerve were recorded distally. RESULTS: The spread phenomenon occurred in 73 of 160 arms (46%), and the SNAP amplitude increased due to contamination of the radial SNAP up to 6.7 times the genuine LAC SNAP. In 10 arms (6%), the spread started before the LAC SNAP was saturated, and the genuine LAC SNAP was unknown due to an anatomical variation in at least 1 arm. CONCLUSIONS: Without monitoring distal radial SNAPs, the spread phenomenon will remain unrecognized. This pitfall undermines the reliability of the test.
Subject(s)
Evoked Potentials/physiology , Neural Conduction/physiology , Radial Nerve/physiology , Skin/innervation , Adult , Age Factors , Aged , Aged, 80 and over , Biophysics , Electric Stimulation , Electromyography , Female , Healthy Volunteers , Humans , Male , Middle Aged , Young AdultABSTRACT
INTRODUCTION: It is generally believed that a shorter stimulus duration is less painful in nerve conduction studies (NCS). We investigated whether a shorter duration stimulus is actually less painful when the same physiological effect, such as supramaximal stimulation, is achieved in motor NCS. METHODS: The tibial nerve was stimulated at the ankle in 14 control subjects and the median nerve at the wrist in 20 subjects. Two stimulations of different durations were given blindly, and each subject was asked to report which was more painful. RESULTS: A 0.2-ms-duration stimulus was significantly less painful than those with longer or shorter durations for the tibial nerve. For the median nerve, the 0.05- and 0.2-ms durations were equally less painful than a 1-ms-duration stimulus. CONCLUSIONS: As a common duration for motor NCS, 0.2 ms seems appropriate, because the tibial nerve stimulation was more painful than the median nerve stimulation.
Subject(s)
Median Nerve/physiopathology , Neural Conduction/physiology , Pain/physiopathology , Tibial Nerve/physiopathology , Adult , Electric Stimulation , Female , Humans , Male , Middle Aged , Pain Measurement , Reaction Time/physiologyABSTRACT
INTRODUCTION: The frequent observation of high-amplitude and long-duration motor unit potentials (MUPs) in inclusion body myositis (IBM) is problematic, because it may lead to a misdiagnosis of amyotrophic lateral sclerosis (ALS). OBJECTIVE: To document the diagnostic utility of EMG from the flexor digitorum profundus (FDP) muscle for IBM. METHODS: Quantitative analyses of MUP parameters were performed in the FDP and biceps brachii (BB) muscles from 7 biopsy-confirmed IBM patients. RESULTS: In the FDP muscle, all MUP parameters were significantly decreased in IBM patients, which indicated the predominance of low-amplitude and short-duration MUPs in this muscle. In the BB muscle, most parameters were increased, suggesting the frequent contamination of high-amplitude and long-duration MUPs. CONCLUSIONS: Low-amplitude MUPs in the FDP muscle indicate the presence of an advanced myopathy in this muscle that was extremely weak for all subjects. Examining the FDP muscle would reduce the chance of misdiagnosing IBM as ALS.
Subject(s)
Amyotrophic Lateral Sclerosis/diagnosis , Electromyography/methods , Forearm/physiopathology , Muscle, Skeletal/physiopathology , Myositis, Inclusion Body/diagnosis , Aged , Aged, 80 and over , Amyotrophic Lateral Sclerosis/physiopathology , Diagnosis, Differential , Diagnostic Errors , Female , Humans , Male , Middle Aged , Myositis, Inclusion Body/physiopathologyABSTRACT
INTRODUCTION: The role of fasciculation potentials (FPs) in the diagnosis of amyotrophic lateral sclerosis (ALS) has been underrated. The Awaji algorithm has restored the value of FPs. Our aim was to test the diagnostic yield of the Awaji algorithm, with consideration of FPs. METHODS: Subjects consisted of 139 consecutive ALS patients retrospectively enrolled over 5 years. At presentation we evaluated the diagnostic categories using the revised El Escorial Criteria (R-EEC) and the Awaji algorithm. RESULTS: The percentage of patients classified as confirmed ALS, clinically probable (laboratory-supported), or higher was 43% using the R-EEC and 37% using the Awaji algorithm. Thirteen patients with upper motor neuron signs only in one body region showed a decrease in their category using the Awaji algorithm. FPs were observed in 89% of ALS patients and were frequent in proximal muscles. CONCLUSION: The sensitivity of the Awaji algorithm is lower than that of the R-EEC.
Subject(s)
Action Potentials/physiology , Algorithms , Amyotrophic Lateral Sclerosis/complications , Fasciculation/diagnosis , Fasciculation/etiology , Adult , Aged , Aged, 80 and over , Electromyography , Female , Humans , Longitudinal Studies , Male , Middle Aged , Retrospective Studies , Sensitivity and SpecificityABSTRACT
OBJECTIVE: To document the incidence and effects of a previously unreported pitfall during routine antidromic sensory nerve conduction study (SCS) of the ulnar nerve: the spread of the wrist stimulation to the dorsal ulnar cutaneous (DUC) branch. METHODS: The subjects consisted of 20 healthy volunteers. An antidromic sensory nerve action potential (SNAP) was recorded over the proximal interphalangeal joint of the little finger, and the DUC response was monitored over the dorsum of hand to check for the occurrence of this spread. RESULTS: The spread occurred in all subjects, which caused a 4-87% increase in the SNAP amplitude. The likelihood that this spread may occur during routine SCS varied among the subjects, and also within an individual subject depending on minute shifts of the stimulating site. Selective stimulation of the ulnar main trunk up to maximal intensity without spread to the DUC was not achieved despite every effort in two subjects. CONCLUSIONS: This spread phenomenon may occur frequently during routine antidromic SCS, but would not be recognized without monitoring the DUC response. SIGNIFICANCE: This pitfall may interfere with the reproducibility of the SNAP amplitude, and also with the diagnosis of ulnar neuropathy at the wrist.