Krooniline sinusiit tsüstilise fibroosi korral haigusjuhu näitel

Tsüstiline fibroos (TF) on autosoom-retsessiivselt päritav haigus, mis põhjustab tihkete sekreetide teket kogu kehas. TFi korral esineb sagedasti, peaaegu 100%-l juhtudest krooniline rinosinusiit (KRS). Samuti on TF sagedasim ninapolüpoosi põhjustaja lastel ning ninapolüpoosiga lapsi tuleks kindlasti TFi suhtes uurida. Tsüstilise fibroosiga seotud KRSi (TF-KRS) haiged alluvad halvasti medikamentoossele ravile. Ninakõrvalkoobaste endoskoopiline operatsioon (FESS) on ohutu ja tõhus ravimeetod nii lastele kui ka täiskasvanutele ning parandab oluliselt KRSi-haigete elukvaliteeti. TF-KRSi korral rakendatakse laiendatud maksillaarset antrotoomiat, mis hõlbustab postoperatiivset lavaaži. On tõendatud, et ka asümptomaatilistele TF-KRSi patsientidele tuleks rakendada FESSi, mis võimaldab eemaldada ninakõrvalkoobastes pesitsevad patogeensed mikroobid. Eesti Arst 2018; 97(7):375–37

Krooniline sinusiit tsüstilise fibroosi korral haigusjuhu näitel

Tsüstiline fibroos (TF) on autosoom-retsessiivselt päritav haigus, mis põhjustab tihkete sekreetide teket kogu kehas. TFi korral esineb sagedasti, peaaegu 100%-l juhtudest krooniline rinosinusiit (KRS). Samuti on TF sagedasim ninapolüpoosi põhjustaja lastel ning ninapolüpoosiga lapsi tuleks kindlasti TFi suhtes uurida. Tsüstilise fibroosiga seotud KRSi (TF-KRS) haiged alluvad halvasti medikamentoossele ravile. Ninakõrvalkoobaste endoskoopiline operatsioon (FESS) on ohutu ja tõhus ravimeetod nii lastele kui ka täiskasvanutele ning parandab oluliselt KRSi-haigete elukvaliteeti. TF-KRSi korral rakendatakse laiendatud maksillaarset antrotoomiat, mis hõlbustab postoperatiivset lavaaži. On tõendatud, et ka asümptomaatilistele TF-KRSi patsientidele tuleks rakendada FESSi, mis võimaldab eemaldada ninakõrvalkoobastes pesitsevad patogeensed mikroobid. Eesti Arst 2018; 97(7):375–37

Rinosinusiidi diagnostika ja ravi – ülevaade ravijuhenditest ja konsensusdokumentidest

Rinosinusiit on nina ja ninakõrvalurgete põletik. Haigus jagatakse sümptomite kestuse järgi ägedaks (sümptomid vähem kui 12 nädalat) ja krooniliseks (sümptomid üle 12 nädala) vormiks. Rinosinusiidi diagnoosimiseks peab esinema kaks või enam põhisümptomit. Kroonilist vormi saab diagnoosida siis, kui sümptomitele lisaks esinevad haiguslikud muutused ka endoskoopial või kompuutertomograafilisel uuringul.Kroonilisel rinosinusiidil on suur mõju elukvaliteedile. Selle sotsiaal-majanduslik koormus ühiskonnale on võrreldav teiste krooniliste haigustega nagu krooniline obstruktiivne kopsuhaigus, astma ja diabeet. Täpne haiguslevimus pole tulenevalt eri uuringutes kasutatud erinevatest diagnoosikriteeriumitest täpselt teada. Küsitlusuuringute järgi on levimus USAs 14–16% ja Euroopas 6,9–27,1%.Viimasel ajal on avaldatud mitmeid ravijuhendeid ja konsensusdokumente eesmärgiga anda tõenduspõhiseid ravisoovitusi ja ühtlustada haiguse käsitlust erinevates riikides. Artiklis on esitatud ülevaade ilmunud juhenditest ning antud nende põhjal ravi- ja diagnostikasoovitusi. Eesti Arst 2017; 96(10):597–60

Kroonilise rinosinusiidi bioloogiline ravi

Krooniline rinosinusiit on nina ja ninakõrvalkoobaste põletik kestusega üle 12 nädala. See haigus mõjutab sageda esinemise tõttu paljude elukvaliteeti ja põhjustab kulusid meditsiinisüsteemile. Senise ravi nurgakivid on nii paiksed kui ka süsteemsed kortikosteroidid, millest esimesed ei anna kõikidele patsientidele soovitud ravitoimet ning viimastel on jällegi hulgaliselt raskeid kõrvaltoimeid. Tõenäoliseks tuleviku ravisuunaks kroonilise rinosinusiidi patsientidel on monokloonsete antikehade kasutusele võtmine. Viimastel aastatel on tehtud mitmeid ravimiuuringuid, mille tulemusi on järjest avalikustatud

Repeated Administration of D-Amphetamine Induces Distinct Alterations in Behavior and Metabolite Levels in 129Sv and Bl6 Mouse Strains

The main goal of the study was to characterize the behavioral and metabolomic profiles of repeated administration (for 11 days) of d-amphetamine (AMPH, 3 mg/kg i. p.), indirect agonist of dopamine (DA), in widely used 129S6/SvEvTac (129Sv) and C57BL/6NTac (Bl6) mouse strains. Acute administration of AMPH (acute AMPH) induced significantly stronger motor stimulation in Bl6. However, repeated administration of AMPH (repeated AMPH) caused stronger motor sensitization in 129Sv compared acute AMPH. Body weight of 129Sv was reduced after repeated saline and AMPH, whereas no change occurred in Bl6. In the metabolomic study, acute AMPH induced an elevation of isoleucine and leucine, branched chain amino acids (BCAA), whereas the level of hexoses was reduced in Bl6. Both BCAAs and hexoses remained on level of acute AMPH after repeated AMPH in Bl6. Three biogenic amines [asymmetric dimethylarginine (ADMA), alpha-aminoadipic acid (alpha-AAA), kynurenine] were significantly reduced after repeated AMPH. Acute AMPH caused in 129Sv a significant reduction of valine, lysophosphatidylcholines (lysoPC a C16:0, lysoPC a C18:2, lysoPC a C20:4), phosphatidylcholine (PC) diacyls (PC aa C34:2, PC aa C36:2, PC aa C36:3, PC aa C36:4) and alkyl-acyls (PC ae C38:4, PC ae C40:4). However, repeated AMPH increased the levels of valine and isoleucine, long-chain acylcarnitines (C14, C14:1-OH, C16, C18:1), PC diacyls (PC aa C38:4, PC aa C38:6, PC aa C42:6), PC acyl-alkyls (PC ae C38:4, PC ae C40:4, PC ae C40:5, PC ae C40:6, PC ae C42:1, PC ae C42:3) and sphingolipids [SM(OH)C22:1, SM C24:0] compared to acute AMPH in 129Sv. Hexoses and kynurenine were reduced after repeated AMPH compared to saline in 129Sv. The established changes probably reflect a shift in energy metabolism toward lipid molecules in 129Sv because of reduced level of hexoses. Pooled data from both strains showed that the elevation of isoleucine and leucine was a prominent biomarker of AMPH-induced behavioral sensitization. Simultaneously a significant decline of hexoses, citrulline, ADMA, and kynurenine occurred. The reduced levels of kynurenine, ADMA, and citrulline likely reflect altered function of N-methyl-D-aspartate (NMDA) and NO systems caused by repeated AMPH. Altogether, 129Sv strain displays stronger sensitization toward AMPH and larger variance in metabolite levels than Bl6

Image_5_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_1_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpeg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_3_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpeg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p

Image_4_Treatment with the dual-incretin agonist DA-CH5 demonstrates potent therapeutic effect in a rat model of Wolfram Syndrome.jpg

AimWolfram Syndrome (WS) is a rare condition caused by mutations in Wfs1, with a poor prognosis and no cure. Mono-agonists targeting the incretin glucagon-like-peptide 1 (GLP-1) have demonstrated disease-modifying potential in pre-clinical and clinical settings. Dual agonists that target GLP-1 and glucose-dependent insulinotropic polypeptide (GIP-1) are reportedly more efficacious; hence, we evaluated the therapeutic potential of dual incretin agonism in a loss-of-function rat model of WS.MethodsEight-month-old Wfs1 knock-out (KO) and wild-type control rats were continuously treated with either the dual agonist DA-CH5 or saline for four months. Glycemic profile, visual acuity and hearing sensitivity were longitudinally monitored pre-treatment, and then at 10.5 and 12 months. Pancreata and retina were harvested for immunohistological analysis.ResultsDA-CH5 therapy reversed glucose intolerance in KO rats and provided lasting anti-diabetogenic protection. Treatment also reversed intra-islet alterations, including reduced endocrine islet area and β-cell density, indicating its regenerative potential. Although no rescue effect was noted for hearing loss, visual acuity and retinal ganglion cell density were better preserved in DA-CH5-treated rats.ConclusionWe present preclinical evidence for the pleiotropic therapeutic effects of long-term dual incretin agonist treatment; effects were seen despite treatment beginning after symptom-onset, indicating reversal of disease progression. Dual incretins represent a promising therapeutic avenue for WS patients.</p