bromochloroacetic-acid and Pain

Pachyonychia congenita (PC) is an autosomal dominant genodermatosis caused by heterozygous mutations in any one of the genes encoding the differentiation-specific keratins K6a, K6b, K16, or K17. The main clinical features of the condition include painful and highly debilitating plantar keratoderma, hypertrophic nail dystrophy, oral leukokeratosis, and a variety of epidermal cysts. Although the condition has previously been subdivided into PC-1 and PC-2 subtypes, the phenotypic characterization of 1,000 mutation-verified PC patients enrolled in the International PC Research Registry, coordinated by the patient advocacy group PC Project, shows that there is considerable overlap between these subtypes. Thus, a new genotypic nomenclature is proposed, in which PC-6a represents a patient carrying a mutation in the K6a gene, etc. Although a rare disorder, PC represents a good model for therapy development, and international efforts are ongoing to develop and deliver siRNA, gene, correction, small molecule, and other strategies to treat this painful, disabling skin condition. The special relationship between PC Project and the PC research community has greatly accelerated the development pathway from gene identification to clinical trials in only a few years and represents a paradigm of hope for other orphan diseases.

Topics: Ectodermal Dysplasia; Humans; Keratins; Keratoderma, Palmoplantar; Mutation; Pachyonychia Congenita; Pain

Endometriosis is a prevalent gynecologic disease, defined by dysfunctional endometrium-like lesions outside of the uterine cavity. These lesions are presumably established via retrograde menstruation, i.e., endometrial tissue that flows backwards during menses into the abdomen and deposits on the organs. As ongoing pain is one of the main pain symptoms of patients, an animal model that illuminates this problem is highly anticipated. In the present study, we developed and validated a rat model for ongoing endometriosis-associated pain. First, menstrual endometrial tissue was successfully generated in donor rats, as validated by gross examination, histology and qPCR. Next, endometriosis was induced in recipient animals by intraperitoneal injection of menstrual tissue. This resulted in neuro-angiogenesis as well as established endometriosis lesions, which were similar to their human counterparts, since epithelial and stromal cells were observed. Furthermore, significant differences were noted between control and endometriosis animals concerning bodyweight and posture changes, indicating the presence of ongoing pain in animals with endometriosis. In summary, a rat model for endometriosis was established that reliably mimics the human pathophysiology of endometriosis and in which signs of ongoing pain were detected, thus providing a new research tool for therapy development.

Topics: Animals; Disease Models, Animal; Endometriosis; Endometrium; Female; GAP-43 Protein; Keratins; Menstruation; Pain; Rats; Stromal Cells; Vimentin

The molecular mechanism of the local hypersensitivity reactions to wasp venom including dermal necrosis remains an enigma regardless of the numerosity of the reported cases. In this study, we discovered a new membrane disrupting toxin, VESCP-M2 responsible for tissue damage symptoms following Vespa mandarinia envenomation. Electrophysiological assays revealed a potent ability of VESCP-M2 to permeate the cell membrane whereas in vivo experiments demonstrated that VESCP-M2 induces edema, pain and dermal necrosis characterized by the presence of morphological and behavioral phenotypes, pro-inflammatory mediators, biomarkers as well as the disruption of dermal tissue. This study presents the molecular mechanism and symptom-related function of VESCP-M2 which may form a basis for prognosis as well as therapeutic interventions.

Topics: Amino Acid Sequence; Animals; Apolipoprotein A-I; Cell Membrane; CHO Cells; Cricetulus; Edema; HEK293 Cells; HeLa Cells; Human Umbilical Vein Endothelial Cells; Humans; Hypersensitivity; Keratins; Mice, Inbred BALB C; Mice, Nude; Necrosis; Pain; Peptides; Wasp Venoms; Wasps

Topics: Biomarkers, Tumor; Endometrial Neoplasms; Female; Gallbladder Neoplasms; Humans; Immunohistochemistry; Keratins; Middle Aged; Pain; Positron-Emission Tomography; Radiography, Abdominal; Receptors, Estrogen; Receptors, Progesterone; Tomography, X-Ray Computed; Ultrasonography; Vimentin

Pachyonychia congenita (PC) is a skin disorder resulting from mutations in keratin (K) proteins including K6a, K6b, K16, and K17. One of the major symptoms is painful plantar keratoderma. The pathogenic sequelae resulting from the keratin mutations remain unclear.. To better understand PC pathogenesis.. RNA profiling was performed on biopsies taken from PC-involved and uninvolved plantar skin of seven genotyped PC patients (two K6a, one K6b, three K16, and one K17) as well as from control volunteers. Protein profiling was generated from tape-stripping samples.. A comparison of PC-involved skin biopsies to adjacent uninvolved plantar skin identified 112 differentially-expressed mRNAs common to patient groups harboring K6 (i.e., both K6a and K6b) and K16 mutations. Among these mRNAs, 25 encode structural proteins including keratins, small proline-rich and late cornified envelope proteins, 20 are related to metabolism and 16 encode proteases, peptidases, and their inhibitors including kallikrein-related peptidases (KLKs), and serine protease inhibitors (SERPINs). mRNAs were also identified to be differentially expressed only in K6 (81) or K16 (141) patient samples. Furthermore, 13 mRNAs were identified that may be involved in pain including nociception and neuropathy. Protein profiling, comparing three K6a plantar tape-stripping samples to non-PC controls, showed changes in the PC corneocytes similar, but not identical, to the mRNA analysis.. Many differentially-expressed genes identified in PC-involved skin encode components critical for skin barrier homeostasis including keratinocyte proliferation, differentiation, cornification, and desquamation. The profiling data provide a foundation for unraveling the pathogenesis of PC and identifying targets for developing effective PC therapeutics.

Topics: Down-Regulation; Enzymes; Gene Expression Profiling; Humans; Keratin-16; Keratin-17; Keratin-6; Keratins; Oligonucleotide Array Sequence Analysis; Pachyonychia Congenita; Pain; RNA, Messenger; Transcriptome; Up-Regulation

Tibia fracture in rats results in chronic vascular and nociceptive changes in the injured limb resembling complex regional pain syndrome (CRPS) and up-regulates expression of interleukin 1β (IL-1β), interleukin IL-6 (IL-6), tumor necrosis factor-α (TNF-α), and nerve growth factor-β (NGF-β) in the hindpaw skin. When fractured rats are treated with cytokine or NGF inhibitors nociceptive sensitization is blocked. Because there is no leukocyte infiltration in the hindpaw skin we postulated that resident skin cells produce the inflammatory mediators causing nociceptive sensitization after fracture. To test this hypothesis rats underwent distal tibia fracture and hindlimb casting for 4 weeks, then the hindpaw skin was harvested and immunostained for keratin, cytokines and NGF. BrdU staining was used to evaluate cell proliferation. Hindpaw nociceptive thresholds, edema, and temperature were tested before and up to 96h after intraplantar injections of IL-6 and TNF-α. Tibia fracture caused keratinocyte activation, proliferation, and up-regulated IL-1β, IL-6, TNF-α and NGF-β protein expression in the hindpaw keratinocytes. Local injections of IL-6 and TNF-α induced hindpaw mechanical allodynia lasting for several days and modest increases in temperature and edema. These data indicate that activated keratinocytes proliferate and express IL-1β, IL-6, TNF-α, and NGF-β after fracture and that excess amounts of inflammatory mediators in the skin cause sustained nociceptive sensitization. This is the first study demonstrating in vivo keratinocyte expression of IL-6, TNF-α and NGF-β in a CRPS model and we postulate that the keratinocyte is the primary cellular source for the inflammatory signals mediating cutaneous nociceptive sensitization in early CRPS.

Topics: Analysis of Variance; Animals; Body Temperature; Cell Proliferation; Cytokines; Dose-Response Relationship, Drug; Immunohistochemistry; Inflammation; Inflammation Mediators; Keratinocytes; Keratins; Male; Nerve Growth Factor; Pain; Rats; Rats, Sprague-Dawley; Tibial Fractures

Topics: Adult; Breast Neoplasms; Carcinoembryonic Antigen; Diagnosis, Differential; Female; Humans; Immunohistochemistry; Keratins; Nipples; Pain; Sweat Gland Neoplasms; Syringoma

To elucidate the possibility that autoantibodies to filaggrin, detected in patients with early RA (having a disease duration of not more than one year), may predict joint destruction assessed after five years of observation.. This is a 5 yr extension of a previous study (1) of 112 consecutive patients with early RA. Serum antifilaggrin autoantibodies were detected by immunoblotting (AFA) and by indirect immunofluorescence ("AKA"). DAS28, pain on a VAS. HAQ, and CRP were measured. Plain X-ray films were taken from hands and forefeet and a Larsen score was calculated.. Ninety-two of the original 112 patients had baseline X-rays available and constituted the study material. At 5 year follow-up, 67 of these 92 have been assessed and for 63 of these X-rays were available. For the whole patient material, significant radiological progression, measured by Larsen scores, occurred while disease activity and function (pain VAS, DAS28, CRP, and HAQ) improved significantly over five years. The groups of patients having AFA or "AKA" at baseline had significantly (p=0.006 and p<0.001, respectively) higher Larsen scores five years later than the groups without these antibodies. No clear relation of these antibodies to disease activity or function was demonstrated, except that the group of patients with "AKA" had significantly higher median CRP (p=0,003) after five years.. The present study shows that antifilaggrin autoantibodies may predict radiological progression. The prognostic value of these antibodies will be further evaluated in relation to other potential markers in a larger patient material.

Topics: Arthritis, Rheumatoid; Arthrography; Autoantibodies; C-Reactive Protein; Disability Evaluation; Disease Progression; Female; Filaggrin Proteins; Fluorescent Antibody Technique, Indirect; Foot; Hand; Health Status; Humans; Immunoblotting; Intermediate Filament Proteins; Joints; Keratins; Male; Middle Aged; Pain; Rheumatoid Factor; Severity of Illness Index; Surveys and Questionnaires

The retinal pigment epithelium (RPE) can undergo reactive hyperplasia and metaplasia following a variety of ocular insults. However, true neoplasms of the RPE are rare. We report a case of a papillary adenocarcinoma of the RPE arising in the blind staphylomatous right eye of a 79-year-old woman with a long history of bilateral posterior staphylomas who was seen with increasing pain and exophthalmos of the right eye. Findings from ultrasonography and computed tomography demonstrated linear calcification consistent with osseous metaplasia of the RPE. Progression of the exophthalmos and worsening exposure keratitis led to enucleation of the eye. Gross pathology showed a 79-mm-long globe. Histopathologic findings revealed a largely amelanotic papillary adenocarcinoma arising from the RPE. Positive immunoreactivity for cytokeratin supported the epithelial origin of the tumor. Adenocarcinoma of the RPE is rare but may develop in a blind eye.

Topics: Adenocarcinoma, Papillary; Aged; Biomarkers, Tumor; Blindness; Calcinosis; Exophthalmos; Eye Enucleation; Female; Humans; Keratins; Magnetic Resonance Imaging; Metaplasia; Pain; Pigment Epithelium of Eye; Retinal Neoplasms; Scleral Diseases; Tomography, X-Ray Computed

Topics: Animals; Animals, Genetically Modified; Cloning, Molecular; Disease Models, Animal; Human Growth Hormone; Humans; Hyperalgesia; Keratins; Mice; Nerve Growth Factors; Pain; Promoter Regions, Genetic; Rats; Recombinant Fusion Proteins; Regulatory Sequences, Nucleic Acid