Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.
- MeSH
- alpha-Galactosidase * administration & dosage therapeutic use MeSH
- Adult MeSH
- Enzyme Replacement Therapy * methods MeSH
- Fabry Disease * drug therapy MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Polyethylene Glycols administration & dosage MeSH
- Recombinant Proteins * administration & dosage therapeutic use MeSH
- Drug Administration Schedule MeSH
- Aged MeSH
- Sphingolipids blood MeSH
- Trihexosylceramides blood MeSH
- Treatment Outcome MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Young Adult MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase III MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
The outcomes of alpha-mannosidosis after hematopoietic stem cell transplantation (HSCT) are incompletely described. This retrospective multi-center study evaluated the outcomes of patients who underwent HSCT for their alpha-mannosidosis after 2010. Twenty-one children (11 females) with enzymatically and/or genetically confirmed alpha-mannosidosis, diagnosed at a mean age of 14 months (0-60 months), were included. The median age at HSCT was 3.9 years (10 months to 13.3 years) with a median follow-up of 2.3 years (0.3-14.1 years). Seventy-four percent (14/19) of patients received an unrelated graft while the rest had a matched sibling donor. Primary engraftment was reached in 17 of 21 patients; four patients required a second HSCT with successful subsequent engraftment. Nine patients had severe post-HSCT infections, five patients developed acute graft-versus-host disease (GvHD) (> = grade II), and one patient had chronic GvHD. No patient died during follow-up. Seven out of ten patients received enzyme replacement therapy both pre- and post-HSCT. Among children with clinical symptoms, improvement was documented in hepatomegaly (40% of patients before HSCT, down to 10% after), recurrent infections (62%/30%), and hearing disorder (85%/65%). In 13 patients with developmental data, outcomes after HSCT suggested at least mild delays persisted post-HSCT in the majority (85%), with some trends of higher functioning with earlier treatment. Findings suggest HSCT has shown notable improvements in safety and is associated with clinical benefit in alpha-mannosidosis. Neurodevelopmental findings require longer-term study to account for phenotypic diversity.
- MeSH
- alpha-Mannosidosis * therapy diagnosis complications MeSH
- Child MeSH
- Enzyme Replacement Therapy MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Follow-Up Studies MeSH
- Graft vs Host Disease etiology MeSH
- Child, Preschool MeSH
- Retrospective Studies MeSH
- Hematopoietic Stem Cell Transplantation * adverse effects methods MeSH
- Treatment Outcome MeSH
- Check Tag
- Child MeSH
- Infant MeSH
- Humans MeSH
- Adolescent MeSH
- Male MeSH
- Child, Preschool MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
BACKGROUND: Bordetella pertussis isolates which do not express some of acellular pertussis vaccine (aPv) antigens, e.g. pertactin (PRN), have been increasingly reported in countries using aPvs. In Finland, primary pertussis vaccination with whole-cell vaccine was replaced by aPv containing pertussis toxin (PT) and filamentous hemagglutinin (FHA) in 2005 and then by aPv containing PT, FHA, and PRN in 2009. We aimed to study alterations in the expression of FHA, PRN, and PT, three antigens included in aPvs and adenylate cyclase toxin (ACT) not included in current aPvs, among Finnish isolates collected during 1991-2020. METHODS: Of 904 isolates collected by the Finnish Reference Laboratory for Pertussis during 1991-2020, 302 were randomly included. An adapted, monoclonal antibody based, antigen expression ELISA, including the culture of B. pertussis in Stainer-Scholte medium, was performed to quantify the expression of ACT, FHA, PRN, and PT of each isolate. ACT activity was also measured for 16 isolates. Arbitrary units were used for comparing levels of each antigen expression of isolates grouped in every five years. FINDINGS: Following the implementation of aPv in 2005, B. pertussis isolates exhibited a 1.75-fold increase for FHA (p < 0.001) and a 1.5-fold increase for ACT (p < 0.0041) expression until 2020. No FHA or ACT deficient isolates were detected. As the number of PRN deficient isolates has significantly increased with the time, the amount of PRN produced by the positive isolates has also started to decrease, especially after the use of aPv containing PRN. During this period, fluctuations in PT expression were observed. INTERPRETATION: The study demonstrated that in response to aPv-induced selection pressure, different types of selection of B. pertussis has occurred. For FHA and ACT, a steady increase in their production is observed, whereas the frequency of PRN deficient isolates is increased with time.
- MeSH
- Vaccines, Acellular immunology MeSH
- Adenylate Cyclase Toxin immunology MeSH
- Antigens, Bacterial * immunology MeSH
- Adhesins, Bacterial MeSH
- Bordetella pertussis * immunology isolation & purification MeSH
- Enzyme-Linked Immunosorbent Assay MeSH
- Virulence Factors, Bordetella immunology MeSH
- Humans MeSH
- Whooping Cough * prevention & control immunology microbiology MeSH
- Pertussis Vaccine * immunology administration & dosage MeSH
- Pertussis Toxin immunology MeSH
- Bacterial Outer Membrane Proteins immunology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Geographicals
- Finland MeSH
BACKGROUND: Alpha-mannosidosis is a rare recessive lysosomal storage disorder with progressive multi-systemic impacts. In the absence of standardized monitoring protocols, there is insufficient understanding of disease progression over time. This study explored the evolution of the burden of illness and quality of life (QoL) experienced by patients with alpha-mannosidosis via an international patient and caregiver-based survey. The online survey was distributed to adult patients/caregivers of patients ≥ 10 years old. It included visual analogue scales (VAS; timepoints 5 years ago and now), multiple choice, and open text questions. We report a subset of functional and QoL data: walking ability, pain/discomfort, ability to self-care, and mental health. RESULTS: Analyses include 51 responses from 18 countries: 26 patients were on velmanase alfa enzyme replacement therapy (ERT), seven had been treated with hematopoietic stem cell transplantation (HSCT) and 18 were untreated patients (UP). Over 5 years, VAS scores showed the least decline in walking ability for HSCT patients (+ 0.1 ± 1.9) compared to patients receiving ERT (+ 0.7 ± 1.2) and UP (+ 1.8 ± 2.0). A trend towards improvement in pain was only observed for those on ERT (-0.2 ± 2.0), both for pediatric and adult patients. Ability to self-care improved for patients treated with HSCT (-1.0 ± 1.8) and slightly improved with ERT (-0.3 ± 1.5) but worsened for UP (+ 0.6 ± 0.9). Similarly, a trend towards improvement in mental health scores was observed for patients on ERT (-0.4 ± 2.2). CONCLUSIONS: Alpha-mannosidosis is associated with a substantial and progressive burden in UP, including deterioration in walking ability, pain, self-care and mental health. The survey results suggest that treatment with ERT or HSCT may slow this natural progression of alpha-mannosidosis, with these patients following a different disease trajectory to those solely receiving supportive care. This study could inform the natural pathway of alpha-mannosidosis to recognize patients' needs, courses of care, and the design of interventional studies.
- MeSH
- alpha-Mannosidosis * physiopathology therapy MeSH
- Pain * physiopathology MeSH
- Adult MeSH
- Mental Health MeSH
- Enzyme Replacement Therapy MeSH
- Quality of Life MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Caregivers MeSH
- Self Care MeSH
- Surveys and Questionnaires MeSH
- Hematopoietic Stem Cell Transplantation MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Ecto-5'-nucleotidase (CD73) is a novel target in cancer (immuno)therapy. Its blockade prevents the formation of immunosuppressive and cancer-promoting adenosine from AMP. Here, we report on the development of a series of small molecules that mimic adenine nucleotides, in which the ribose moiety was replaced by an alkyl chain. Its length was found to be crucial for potency. A crystal structure of the N6-disubstituted acyclic ADP analog 26 (N6-benzyl,N6-methyladenine-9-yl)pentyloxydiphosphonate) in complex with human CD73 revealed that the flexible pentyl linker adopts to interdomain rotation angles differing by up to 18.5°. The most potent CD73 inhibitor of the present series was analog 27 (N6-benzyl,N6-methyladenine-9-yl)hexyloxydiphosphonate, PSB-24000) which exhibited submicromolar potency at human CD73 (Ki 563 nM at soluble CD73; Ki 481 nM at membrane-bound CD73 of triple-negative breast cancer cells). Acyclic nucleotide analogs may be advantageous compared to the previously reported nucleotidic CD73 inhibitors due to their high chemical stability, and because less off-target effects are to be expected. The structure-activity relationships discovered in this study provide valuable insights which will be useful for the development of CD73 inhibitors as immunotherapeutic drugs.
- MeSH
- 5'-Nucleotidase * antagonists & inhibitors metabolism MeSH
- Cisplatin chemistry pharmacology MeSH
- GPI-Linked Proteins antagonists & inhibitors metabolism MeSH
- Enzyme Inhibitors * pharmacology chemistry chemical synthesis MeSH
- Humans MeSH
- Models, Molecular MeSH
- Molecular Structure MeSH
- Purine Nucleotides * chemistry pharmacology chemical synthesis MeSH
- Pyrimidine Nucleotides * chemistry pharmacology chemical synthesis MeSH
- Dose-Response Relationship, Drug MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Cystická fibróza je vzácné onemocnění, u kterého na podkladě mutace proteinu CFTR (fibrosis transmembrane conductance regulator, CFTR) dochází ke zvyšování viskozity hlenů exokrinních buněk, jenž následně způsobují poruchu funkce až destrukci některých orgánů (plíce, slinivka břišní, játra, střeva, chámovody aj.). Konzervativní léčba se skládá z mukolytik, bronchodilatancií, nekompromisní antibiotické terapie, substituční léčby pankreatických enzymů, suplementace vitaminů, léčbě jaterního selhávání a léčbě ostatních komorbidit a podpůrné terapie. Vysoce účinné modulátory CFTR významně zlepšují plicní funkce, zlepšují vstřebávání živin a nutriční stav, kvalitu života a v neposlední řadě předpokládanou délku života.
Cystic fibrosis is a rare disease characterized by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) protein. This mutation leads to increased viscosity of mucus in exocrine cells, which subsequently causes dysfunction and possible destruction of various organs (such as the lungs, pancreas, liver, intestines, and vas deferens). Conservative treatment includes mucolytics, bronchodilators, rigorous antibiotic therapy, pancreatic enzyme replacement therapy, vitamin supplementation, treatment of liver failure, management of other comorbidities, and supportive therapy. Highly effective CFTR protein modulators significantly improve lung function, nutrient absorption, nutritional status, quality of life, and, not least, life expectancy.
- Keywords
- ivacaftor,
- MeSH
- Chloride Channel Agonists pharmacology therapeutic use MeSH
- Anti-Bacterial Agents pharmacology therapeutic use MeSH
- Cystic Fibrosis * therapy MeSH
- Enzyme Therapy methods MeSH
- Humans MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator antagonists & inhibitors therapeutic use MeSH
- Check Tag
- Humans MeSH
- Publication type
- Review MeSH
Úvod: Dědičné poruchy metabolismu (DPM) lipidů představují heterogenní skupinu více než 210 různých poruch syntézy, transportu či odbourávání lipoproteinů, mastných kyselin (MK), glycerolu, ketolátek, cholesterolu a komplexních lipidů. Materiál a metody: Diagnostika je závislá na klinickém podezření a indikaci biochemických, metabolických a molekulárních vyšetření, pouze šest poruch β-oxidace MK (FAOD) je součástí laboratorního novorozeneckého screeningu. Výsledky: Klinické projevy DPM lipidů jsou heterogenní a u řady poruch se mohou překrývat. Nejčastější je fami- liární autozomálně dominantní hypercholesterolemie (HeFH) s výskytem 1 : 250. Včasná diagnostika a léčba u dětí s HeFH je nezbytná pro vysoké riziko rozvoje aterosklerózy. Některé DPM lipidů se mohou projevit již embryonálně vrozenými vývojovými vadami, například mikrocefalie, syndaktylie a hypospadie u dětí se Smithovým–Lemliho–Opitzovým syndromem a endogenní poruchou syntézy cholesterolu či kraniofaciální dysmorfie a extrémní hypotonie u dětí se Zellwegerovým syndromem a poruchou peroxisomální biogeneze. Poruchy β-oxidace MK se projevují především v novorozeneckém nebo kojeneckém věku akutními atakami hypoketotických hypoglykemií, hepatomegalií, hepatopatií a kardiomyopatií nebo až později myopatií s epizodickými rhabdomyolýzami při hladovění, infektu nebo vyšší fyzické námaze. Poruchy peroxisomální oxidace MK s velmi dlouhým řetězcem se projeví leukodystrofií nebo myeloneuropatií a adrenální insuficiencí. Poruchy metabolismu lipoproteinů se závažnou hypertriacylglycerolemií s poruchou lipoproteinové lipázy (LPL) se mohou projevit akutní pankreatitidou. Poruchy lysosomálního metabolismu esterů cholesterolu a lipidů v komplexních molekulách (sfingolipidózy) způsobují s výjimkou Fabryho nemoci hepatosplenomegalii, hepatopatii a dyslipidemii. Závažnou klinickou problematikou u Gaucherovy nemoci je obrovská splenomegalie s trombocytopenií, u Niemannovy–Pickovy nemoci typu A, B intersticiální plicní postižení a neuropatie a u typu C porucha vertikálního pohledu a neuropsychiatrická symptomatologie. Fabryho nemoc se v dětství manifestuje angiokeratomy a akroparesteziemi. Závěr: Včasná diagnostika je nezbytná pro úspěšnou léčbu, která zahrnuje úpravu životosprávy a jídelníčku, vyšší pohybovou aktivitu a farmakoterapii u dětí s HeFH či frekventní výživu s přidáním nevařených škrobů u dětí s FAOD. Suplementace MCT oleji se používá u dětí s poruchou β-oxidace MK s dlouhým řetězcem a cholesterolu u poruch biosyntézy cholesterolu. U dětí se sfingolipidózami nebo poruchou metabolismu esterů cholesterolu se podává enzymová substituční terapie či substrát redukční terapie. Transplantace hematopoietických kmenových buněk je indikovaná u chlapců s rizikem rozvoje cerebrální formy X-vázané adrenoleukodystrofie.
Introduction: Inherited disorders of lipid metabolism (IMD) represent a heterogeneous group of >210 different disorders of synthesis, transport or degradation of lipoproteins, fatty acids (FA), glycerol, ketone body, cholesterol, and complex lipids. Material and methods: Diagnosis depends on clinical suspicion and indication of biochemical, metabolic, and molecular investigations, only six disorders of fatty acid oxidation deficiencies (FAOD) are part of the laboratory neonatal screening in the Czech Republic. Results: Clinical manifestations of IMD of lipid metabolism are heterogeneous and may overlap in many disorders. The most common is familial autosomal dominant hypercholesterolemia (HeFH) with an incidence of 1:250. Early diagnosis and treatment in children with HeFH is essential because of the high risk for development of atherosclerosis. Disorders of lipoprotein metabolism with severe hypertriacylglycerolaemia may manifest with acute life-threatening pancreatitis, especially in lipoprotein lipase deficiency. Some IMD of lipid metabolism may manifest in embryonic period resulting in developmental defects as microcephaly, syndactyly, and hypospadia in children with Smith-Lemli-Opitz syndrome or craniofacial dysmorphia and extreme hypotonia in children with Zellweger syndrome. Children with FAOD usually manifest in neonatal period or infancy by acute attacks of hypoketotic hypoglycaemia, hepatomegaly, hepatopathy and cardiomyopathy or later by myopathy with episodic rhabdomyolysis during prolong fasting, infection or increased physical exertion. Disorders of peroxisomal oxidation of very long-chain FA manifest as leukodystrophy or neuromyelopathy and adrenal insufficiency. Disorders of lysosomal metabolism of cholesterol esters and lipids in complex molecules (sphingolipidoses) cause hepatosplenomegaly, hepatopathy and dyslipidaemia, except for Fabry disease. Main clinical problems in Gaucher disease are splenomegaly, tromobocytopenia, and bone disease, in Niemann-Pick disease types A and B interstitial lung involvement and neuropathy, and in type C vertical supranuclear gaze palsy and neuropsychiatric symptomatology. Fabry disease manifests in childhood with angiokeratomas and acroparesthesia. Conclusion: Early diagnosis is essential for successful treatment. It involves change of lifestyle and low-fat diet in children with HeFH and LPL deficiency, frequent feeding supplemented with uncooked starches in FAOD, MCT oil supplementation in very long-chain FAOD and cholesterol supplementation in cholesterol synthesis disorders. Enzyme replacement therapy or substrate reduction therapy are used children with sphingolipidosis and impaired cholesterol ester metabolism. Hematopoietic stem cell transplantation is indicated in males at risk of the cerebral form of X-linked adrenoleukodystrophy.
- MeSH
- Long-Chain-3-Hydroxyacyl-CoA Dehydrogenase MeSH
- Adrenoleukodystrophy diagnosis physiopathology pathology therapy MeSH
- Child MeSH
- Humans MeSH
- Lipoproteins metabolism MeSH
- Peroxisomal Disorders classification physiopathology pathology therapy MeSH
- Lipid Metabolism Disorders * classification physiopathology therapy congenital MeSH
- Sphingolipids MeSH
- Smith-Lemli-Opitz Syndrome diagnosis physiopathology pathology therapy MeSH
- Metabolism, Inborn Errors * classification physiopathology pathology therapy MeSH
- Check Tag
- Child MeSH
- Humans MeSH
- Publication type
- Research Support, Non-U.S. Gov't MeSH
- Review MeSH
Léčebná výměnná plazmaferéza (therapeutic plasma Exchange – TPE) má nezastupitelné místo v léčbě některých typů trombotických mikroangiopatií a je léčbou volby u trombotické trombocytopenické purpury. TPE je podle American Society for Apheresis (ASFA) definována jako terapeutický extrakorporální postup, při kterém je plazma pacienta oddělena od ostatních krevních složek. Jedná se sice o invazivní techniku vyžadující kvalitní žilní přístup, na druhé straně je TPE vysoce bezpečná, a při správném provedení jsou komplikace raritní, lze ji v případě potřeby zahájit během desítek minut a v zásadě nemá žádné reálné kontraindikace. Oddělení plazmy od ostatních složek krve je zajištěno centrifugací nebo membránovou filtrací. Jako náhradní roztok se v různých poměrech a kombinacích používají krystaloidy, 5% roztok albuminu a čerstvě zmražená dárcovská plazma, nebo se v poslední době stále častěji používá plazma ošetřená solvent-detergentem. Během jednoho výkonu se má vyměnit nejméně celý objem plazmy pacienta (total plasma volume – TPV), čímž dojde k výměně, a tedy nahrazení necelých 70 % TPV. Léčba TTP plazmaferézou by měla být zahájena co nejdříve, již při vyslovení podezření na TTP, často ještě před znalostí výsledků aktivity enzymu ADAMTS13. Před zahájením léčby TPE je nutné pamatovat na odběr vzorků krve na vyšetření ADAMTS13 a dalších vyšetření, případně uchování vzorků plazmy, protože interpretace výsledků vzorků odebraných po provedené TPE může být chybná. Účinnost TPE je dána dvěma mechanizmy: 1) odstranění mediátoru onemocnění nebo složek plazmy přispívajících k patogeneze daného stavu; 2) dodání chybějící či nefunkční složky plazmy v případě použití plazmy jako náhradního roztoku. Efektivita TPE se u jednotlivých forem trombotických mikroangiopatií různí, od jednoznačného a promptního efektu u TTP až po nulový efekt u některých forem atypického hemolyticko-uremického syndromu.
Therapeutic plasma exchange (TPE) has an irreplaceable place in the treatment of some types of thrombotic microangiopathies. In TTP, it has become the standard of care. TPE is defined by the American Society for Apheresis (ASFA) as a therapeutic extracorporeal procedure in which the patient‘s plasma is separated from other blood components. Although it is an invasive technique requiring high-quality venous access, TPE is quite safe, and when performed correctly, complications are rare. It can be started within tens of minutes if necessary, and it has essentially no real contraindications. Separation of plasma from other blood components is ensured by centrifugation or membrane filtration. Crystalloids, 5% albumin solution and freshly frozen donor plasma are used as a replacement solution in various proportions and combinations and nowadays, solvent-detergent-treated plasma is used increasingly. At least one total plasma volume (TPV) of the patient should be replaced in one procedure, with less than 70% of the TPV being replaced. It is important to remember to collect blood samples for ADAMTS13 and other tests, or preserve plasma samples, before starting TPE treatment, as interpretation of results from samples collected after TPE may be erroneous. The efficacy of TPE is determined by two mechanisms: 1) removal of the disease mediator or plasma components contributing to the pathogenesis of the condition; 2) delivery of the missing or dysfunctional plasma component when plasma is used as a replacement solution. The efficacy of TPE varies between the various forms of thrombotic microangiopathies, ranging from a clear and prompt effect in TTP to no effect at all in some forms of atypical haemolytic uraemic syndrome.
Despite the adenoids are regularly removed in patients with mucopolysaccharidoses (MPS), the underlying tissue and cellular pathologies remain understudied. We characterized an (immuno)histopathologic and ultrastructural phenotype dominated by lysosomal storage changes in a specific subset of adenotonsillar paracortical cells in 8 MPS patients (3 MPS I, 3 MPS II, and 2 MPS IIIA). These abnormal cells were effectively detected by an antibody targeting the lysosomal membrane tetraspanin CD63. Important, CD63+ storage vacuoles in these cells lacked the monocytes/macrophages lysosomal marker CD68. Such a distinct patterning of CD63 and CD68 was not present in a patient with infantile neurovisceral variant of acid sphingomyelinase deficiency. The CD63+ storage pathology was absent in two MPS I patients who either received enzyme-replacement therapy or underwent hematopoietic stem cells transplantation prior the adenoidectomy. Our study demonstrates novel features of lysosomal storage patterning and suggests diagnostic utility of CD63 detection in adenotonsillar lymphoid tissue of MPS patients.
- MeSH
- Tetraspanin 30 MeSH
- Enzyme Replacement Therapy MeSH
- Humans MeSH
- Lymphoid Tissue pathology MeSH
- Lysosomes MeSH
- Mucopolysaccharidoses * diagnosis drug therapy genetics MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
Exokrinní pankreatická nedostatečnost (EPI – exocrine pancreatic insufficiency) je charakterizována nedostatečnou sekrecí pankreatických trávicích enzymů. Dle mechanistické teorie není nedostatkem pankreatických enzymů v tenkém střevě zajištěno trávení potravy, což je spojeno především s nedostatkem esenciálních mastných kyselin a liposolubilních vitaminů a ve svém důsledku vede k neschopnosti zajistit nutriční a metabolické potřeby organizmu. V diagnostice je standardem stanovení fekální elastázy. Toto stanovení je jednoduché, limitací je malá senzitivita stanovit možné změny pankreatické funkce již v tzv. iniciálních stadiích nemoci. Alternativou vyšetření fekální elastázy je použití dechových testů s využitím mixu triglyceridů označených radioaktivně na uhlíku C13. Test je sice neinvazivní, ale časově náročný a obtížněji dostupný. Klinickými symptomy EPI jsou především takové příznaky, které souvisí s mikrobiálním trávením a následnou malabsorbcí/maldigescí mikro- i makronutrientů. Kromě subjektivního pocitu nadýmání, borborygmů nebo osmotického průjmu jsou častým nálezem nízké hladiny liposolubilních vitaminů a některých stopových prvků. Do obrazu EPI patří i osteoporóza nebo sarkopenie. V terapii EPI je zásadním přístupem dietoterapie a substituce pankreatickými enzymy. Zásadou je podání odpovídající dávky především pankreatické lipázy: 40 000–50 000 jednotek k hlavním jídlům, s aplikací během jídla. Menší jídla (svačiny) jsou substituovány poloviční dávkou. Optimální galenickou formou jsou kapsle s ochranným obalem proti inaktivaci enzymů žaludeční kyselinou solnou před jejich vstupem do duodena. Galenickou formou jsou kapsle s obsahem enzymů v mikročásticích o velikosti 1,0–2,0 mm, které se z kapsle uvolní při vstupu do duodena. Jedná se o tzv. řízenou synchronizaci liberalizace enzymů, které obsahuje kapsle. EPI je stavem v populaci poddiagnostikovaným a podléčeným. Kontrola pacientů tak musí zahrnout kromě zhodnocení celkového klinického stavu i sledování změn, které mohou manifestovat malabsorpci. Nutriční stav je doporučeno sledovat alespoň jednou ročně, a to v pravidelných intervalech.
Exocrine pancreatic insufficiency (EPI) is characterized by insufficient secretion of pancreatic digestive enzymes. According to the mechanistic theory, the lack of pancreatic enzymes in the small intestine does not ensure the digestion of food, which is mainly associated with the lack of essential fatty acids and liposoluble vitamins and, as a result, leads to the inability to ensure the nutritional and metabolic needs of the organism. In diagnostics, the standard is determination of fecal elastase. This determination is simple, the limitation is the low sensitivity to determine possible changes in pancreatic function already in the so-called initial stages of the dis ease. An alternative to fecal elastase testing is the use of breath tests using a mixture of triglycerides, radioactively labeled with carbon C13. Although the test is non-invasive, it is time-consuming and more difficult to access. The clinical symptoms of EPI are mainly those related to microbial digestion and subsequent malabsorption/maldigestion of micro- and macronutrients. In addition to the subjective feeling of bloating, borborygmy or osmotic diarrhea, low levels of liposoluble vitamins and some trace elements are frequent findings. Osteoporosis or sarcopenia belong to the picture of EPI. In EPI therapy, diet therapy and pancreatic enzyme replacement are essential approaches. The principle is to administer an adequate dose, especially of pancreatic lipase: 40,000–50,000 units with main meals, with application during meals. Smaller meals (snacks) are substituted with half the dose. The optimal galenic form is capsules with a protective cover, against the inactivation of enzymes by gastric acid, before they enter the duodenum. The galenic form is capsules containing enzymes in microparticles, 1.0–2.0 mm in size, which are released from the capsule upon entering the duodenum. This is the so-called controlled synchronization of the liberalization of the enzymes contained in the capsule. EPI is an underdiagnosed and undertreated condition in the population. The control of patients must therefore include, in addition to the evaluation of the overall clinical condition, the monitoring of changes that may manifest malabsorption. It is recommended to monitor the nutritional status at least once a year, at regular intervals.
