25 research outputs found
Primary alterations during the development of hidradenitis suppurativa
BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory disease of the apocrine glandârich (AGR) skin region. The initial steps of disease development are not fully understood, despite intense investigations into immune alterations in lesional HS skin. OBJECTIVES: We aimed to systematically investigate the inflammatory molecules involved in three stages of HS pathogenesis, including healthy AGR, nonâlesional HS and lesional HS skin, with the parallel application of multiple mRNA and proteinâbased methods. METHODS: Immune cell counts (T cells, dendritic cells, macrophages), Th1/Th17ârelated molecules (ILâ12B, TBX21, IFNG, TNFA, ILâ17, IL10, ILâ23A, TGFB1, RORC, CCL20), keratinocyteârelated sensors (TLR2,4), mediators (S100A7, S100A8, S100A9, DEFB4B, LCN2, CAMP, CCL2) and proâinflammatory molecules (IL1B, IL6, TNFA, ILâ23A) were investigated in the three groups by RNASeq, RTâqPCR, immunohistochemistry and immunofluorescence. RESULTS: Epidermal changes were already detectable in nonâlesional HS skin; the epidermal occurrence of antimicrobial peptides (AMPs), ILâ1ÎČ, TNFâα and ILâ23 was highly upregulated compared with healthy AGR skin. In lesional HS epidermis, TNFâα and ILâ1ÎČ expression remained at high levels while AMPs and ILâ23 increased even more compared with nonâlesional skin. In the dermis of nonâlesional HS skin, signs of inflammation were barely detectable (vs. AGR), while in the lesional dermis, the number of inflammatory cells and Th1/Th17ârelated mediators were significantly elevated. CONCLUSIONS: Our findings that nonâlesional HS epidermal keratinocytes produce not only AMPs and ILâ1ÎČ but also high levels of TNFâα and ILâ23 confirm the driver role of keratinocytes in HS pathogenesis and highlight the possible role of keratinocytes in the transformation of nonâinflammatory Th17 cells (of healthy AGR skin) into inflammatory cells (of HS) via the production of these mediators. The fact that epidermal TNFâα and ILâ23 appear also in nonâlesional HS seems to prove these cytokines as excellent therapeutic targets
Fabry-betegsĂ©g â terĂĄpiĂĄs ĂștmutatĂł
A Fabry-kĂłr a lizoszomĂĄlis tĂĄrolĂĄsi betegsĂ©gek csoportjĂĄba tartozĂł, X-kromoszĂłmĂĄhoz kötötten, recesszĂv mĂłdon öröklĆdĆ betegsĂ©g, amely a globotriaozilceramid felhalmozĂłdĂĄsĂĄhoz vezet a szervezet legkĂŒlönbözĆbb szöveteiben. A betegsĂ©g elsĆ tĂŒnetei többnyire gyermekkorban jelentkeznek, a progressziĂł sorĂĄn a betegek sĂșlyos szervi kĂĄrosodĂĄsokkal Ă©s korai halĂĄlozĂĄssal szĂĄmolhatnak. ElsĆsorban fĂ©rfiak Ă©rintettek, azonban a betegsĂ©g tĂŒneteit heterozigĂłta nĆk esetĂ©ben is megfigyelhetjĂŒk, de nĂĄluk a kĂłrkĂ©p sĂșlyossĂĄga vĂĄltozĂł, ĂĄltalĂĄban enyhĂ©bb lefolyĂĄsĂș. Az enzimpĂłtlĂł kezelĂ©sek megjelenĂ©se szĂŒksĂ©gessĂ© tette, hogy rĂ©szletes diagnosztikus Ă©s terĂĄpiĂĄs protokollt dolgozzunk ki. A jelen dolgozatban megjelenĆ ajĂĄnlĂĄsokat egy, a magyarorszĂĄgi Fabry-kĂłros betegek kezelĂ©sĂ©ben rĂ©szt vevĆ orvosokbĂłl, a diagnosztika terĂŒletĂ©n dolgozĂł biolĂłgosukbĂłl Ă©s egyĂ©b szakemberekbĆl ĂĄllĂł multidiszciplinĂĄris munkacsoport foglalta össze. A munkacsoport ĂĄttekintette a korĂĄbbi klinikai tanulmĂĄnyokat, a publikĂĄlt vizsgĂĄlatokat Ă©s a közelmĂșltban megjelent nemzetközi Ă©s nemzeti ĂștmutatĂłkat.
|
Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive and the first symptoms usually present in childhood. Consequences of the disease are disability and premature death. The disease in females could be as severe as in males although women may be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline has been summarized by a Hungarian multi-disciplinary working group consisting of physicians who are involved in diagnosis and care of Fabry patients. Previous clinical studies, published articles, and recently established international treatment guidelines were reviewed by the group
Fabry-betegsĂ©g - Diagnosztikai ĂștmutatĂł
A Fabry-kĂłr a lizoszomĂĄlis tĂĄrolĂĄsi betegsĂ©gek csoportjĂĄba tartozĂł, X-kromoszĂłmĂĄhoz kötötten, recesszĂv mĂłdon öröklĆdĆ betegsĂ©g, amely a globotriaosylceramid felhalmozĂłdĂĄsĂĄhoz vezet a szervezet legkĂŒlönbözĆbb szöveteiben. A betegsĂ©g elsĆ tĂŒnetei többnyire gyermekkorban jelentkeznek, a progressziĂł sorĂĄn a betegek sĂșlyos szervi kĂĄrosodĂĄsokkal Ă©s korai halĂĄlozĂĄssal szĂĄmolhatnak. ElsĆsorban fiĂșk Ă©s fĂ©rfiak Ă©rintettek, azonban a betegsĂ©g tĂŒneteit heterozigĂłta nĆk esetĂ©ben is megfigyelhetjĂŒk, de nĂĄluk a kĂłrkĂ©p sĂșlyossĂĄga vĂĄltozĂł, ĂĄltalĂĄban enyhĂ©bb lefolyĂĄsĂș. Az enzimpĂłtlĂł kezelĂ©sek megjelenĂ©se szĂŒksĂ©gessĂ© tette, hogy rĂ©szletes diagnosztikus Ă©s terĂĄpiĂĄs protokollt dolgozzunk ki. A jelen dolgozatban megjelenĆ ajĂĄnlĂĄsokat egy, a magyarorszĂĄgi Fabry-betegek kezelĂ©sĂ©ben aktĂvan rĂ©szt vevĆ orvosokbĂłl, a diagnosztika terĂŒletĂ©n dolgozĂł biolĂłgosukbĂłl Ă©s egyĂ©b szakemberekbĆl ĂĄllĂł multidiszciplinĂĄris munkacsoport foglalta össze. A munkacsoport ĂĄttekintette a korĂĄbbi klinikai tanulmĂĄnyokat, a publikĂĄlt vizsgĂĄlatokat Ă©s a közelmĂșltban megjelent nemzetközi Ă©s nemzeti ĂștmutatĂłkat.
|
Fabry disease is a rare, X-linked lysosomal storage disorder that leads to accumulation of globotriaosylceramide in different tissues of the body. The disease is progressive, first symptoms usually present in childhood. Consequencies of the diseases are disability and premature death. The disease in females could be as severe as in males although women may also be asymptomatic. The possibility of enzyme replacement therapy has made it necessary to elaborate a comprehensive guideline for the diagnosis and treatment follow-up. The guideline was established by a Hungarian multi-disciplinary working group, consisting of physicians who are involved in health care of Fabry patients. Previous clinical studies, published materials, and recently established international treatment guidelines were reviewed by the group
Diagnosis of late-onset Pompe disease and other muscle disorders by next-generation sequencing
Newborn screening for Pompe disease by measuring acid alpha-glucosidase activity using tandem mass spectrometry.
BACKGROUND: Pompe disease, caused by the deficiency of acid alpha-glucosidase (GAA), is a lysosomal storage disorder that manifests itself in its most severe form within the first months of life. Early detection by newborn screening is warranted, since prompt initiation of enzyme replacement therapy may improve morbidity and mortality. We evaluated a tandem mass spectrometry (MS/MS) method to measure GAA activity for newborn screening for Pompe disease. METHODS: We incubated 3.2-mm punches from dried blood spots (DBS) for 22 h with the substrate [7-benzoylamino-heptyl)-{2-[4-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran- 2-yloxy)-phenylcarbamoyl]- ethyl}-carbamic acid tert-butyl ester] and internal standard [7-d(5)-benzoylamino-heptyl)-[2-(4-hydroxy-phenylcarbamoyl)-ethyl]-carbamic acid tertbutyl ester]. We quantified the resulting product and internal standard using MS/MS. We assessed inter- and intrarun imprecision, carryover, stability, and correlation between enzyme activities and hematocrit and punch location and generated a Pompe disease-specific cutoff value using routine newborn screening samples. RESULTS: GAA activities in DBS from 29 known Pompe patients were <2 micromol/h/L. GAA activities in routine newborn screening samples were [mean (SD)] 14.7 (7.2) micromol/h/L (n = 10,279, median 13.3, 95% CI 14.46-14.74 micromol/h/L) and in normal adult samples 9.3 (3.3) micromol/h/L (n = 229, median 9, 95% CI 8.88-9.72 micromol/h/L). GAA activity was stable for 28 days between 37 degrees C and -80 degrees C. Carryover could not be observed, whereas intrarun and interrun imprecision were <10%. The limit of detection was 0.26 micromol/h/L and limit of quantification 0.35 micromol/h/L. CONCLUSIONS: The measurement of GAA activities in dry blood spots using MS/MS is suitable for high-throughput analysis and newborn screening for Pompe disease
Improvement of clinical and immunological parameters after allergen specific immunotherapy in atopic dermatitis
Background: Allergen immunotherapy (AIT) is considered a curative treatment in some atopic diseases, but in AD contradictory clinical results exist and the action of AIT has not been elucidated. In the literature there is no evidence for parallel investigations of permeability barrier, cutaneous, and blood immune responses after AIT in AD. Objectives: The objective was to investigate immune parameters in the blood and skin and to detect clinical, and barrier changes after AIT in AD. Methods: Mild-to-moderate AD patients (n=14) with concomitant allergic rhinitis to house dust mites were selected. All patients received topical treatment, while eight patients were randomly selected for adjuvant AIT also. At baseline and after 6 months clinical, barrier and immunological investigations (serum and skin tests) were performed. In selected patients, biopsies from atopy patch tests (APT) were analysed by immunohistochemistry for ADrelevant immune cells and mediators. Results: In the adjuvant AIT-group, clinical parameters and barrier functions improved significantly. Blood immune parameters displayed no significant changes. Post-AIT APT became negative in all patients in the AIT-group, but remained positive in the non-AIT group. Cutaneous dendritic cell and T cell recruitment decreased significantly after allergen challenge in the AIT-group, but no significant changes in skin or serum immunoglobulin E levels or prick test (SPT) reactivity were detected. Conclusions: AIT is a beneficial adjuvant treatment for sensitized AD patients. AIT improves not only clinical symptoms, but also permeability barrier functions. The effect of AIT on sensitization should be detected by APT, not by SPT