C.35delG/ GJB2 and del(GJB6-D13S1830) mutations in Croatians with prelingual non-syndromic hearing impairment

BACKGROUND: C.35delG/GJB2 mutation is the most frequent genetic cause of deafness in Caucasians. Another frequent mutation in some Caucasian populations is del(GJB6-D13S1830). Both GJB2 and GJB6 genes belong to the same DFNB1 locus and when the two mutations are found in combination in a hearing-impaired person, a digenic pattern of inheritance is suggested. METHODS: We examined 63 Croatian subjects (25 familial and 38 sporadic cases) with prelingual non-syndromic hearing impairment by polymerase chain reaction for the presence of the c.35delG/GJB2 and the del(GJB6-D13S1830) mutations. RESULTS: Of the 63 unrelated hearing-impaired subjects, the mutation c.35delG/GJB2 was found in 21 subjects (33.3%). In 5 of them the mutation was found in the heterozygous state, all of them being compound heterozygotes, as sequencing revealed a second mutation within the coding region of the gene in 3 subjects, and a splice site mutation in 2 subjects. The del(GJB6-D13S1830) mutation was not found in the investigated hearing-impaired Croatian subjects. CONCLUSION: Our results contribute to the knowledge of geographic distribution and population genetics of the GJB2 and GJB6 mutations in the Europeans

Recidivi venske tromboze unatoč “optimalne antikoagulantne terapije” antifosfolipidnog sindroma. Mogu li novi peroralni antikoagulansi riješiti problem ?

The aim was to determine the validity of the international normalized ratio (IN R) and prothrombin time (PT ) as a monitor for warfarin therapy in patients with lupus anticoagulants and recurrent thrombosis, and to investigate alternative approaches to monitoring warfarin therapy and new treatment options in these patients. A case is described of a 63-year-old female with antiphospholipid syndrome and recurrent venous thrombosis despite optimal adjusted warfarin therapy. In patients with lupus anticoagulants, the IN Rs obtained while receiving warfarin vary and often overestimate the extent of anticoagulation, while PT without receiving warfarin is often prolonged. In conclusion, lupus anticoagulants can influence PT and lead to IN R that does not accurately reflect the true level of anticoagulation. Optimizing of (warfarin) oral anticoagulation therapy could be achieved by individual monitoring of anticoagulation effect with a test that is insensitive to lupus anticoagulants (chromogenic factor X assay). Emerging oral anticoagulants, direct thrombin inhibitors and direct factor Xa inhibitors, such as dabigatran and rivaroxaban, with a predictable anticoagulant response and little potential for food or drug interactions, have been designed to be administered in fixed doses without coagulation monitoring and could be the treatment choice for these patients.Cilj je bio analizirati uzroke neuspjeha “optimalno doziranog” varfarina kod prevencije recidiva duboke venske tromboze u bolesnika s antifosfolipidnim sindromom. Opisuje se slučaj 63-godišnje bolesnice s antifosfolipidnim sindromom i recidivima venske tromboze tijekom uzimanja varfarina. Vrijednosti IN R bile su u terapijskim granicama. Analizirali su se patofiziološki mehanizmi nastanka tromboze i literaturni podaci. Rezultati su pokazali kako u bolesnika s pozitivnim lupus antikoagulans (LA) testom vrijednost PV -IN R ne daje pravu sliku protuzgrušavajućeg učinka varfarina. Aktivnost PV je zbog interferencije često lažno smanjena, iako u času mjerenja bolesnik ne uzima varfarin ili drugi antagonist vitamina K. Zaključak je kako prisutnost LA može interferencijom lažno smanjiti aktivnost u PV testu i rezultirati nalazom IN R koji ne odražava pravo stanje protuzgrušavajuće aktivnosti izazvane varfarinom. U tom bi slučaju umjesto PV testa trebalo mjeriti aktivnost faktora Xa kromogenom metodom koja je neosjetljiva na LA. Drugo moguće rješenje bi u bolesnika s antifosfolipidnim sindromom bila zamjena varfarina novim lijekovima, oralnim inhibitorima trombina i faktora X. Ovi lijekovi u fiksnoj dozi s predvidivim te o hrani i lijekovima uglavnom neovisnim protuzgrušavajućim učinkom imaju djelotvornost i nuspojave uglavnom slične varfarinu, ali ne trebaju kontrole IN R

MUTATIONS IN GENE GJB2/CONNEXIN 26 AS THE MOST FREQUENT CAUSE OF IMPAIRED HEARING

Zbog svoje učestalosti i potrebe za ranom dijagnozom, oslabljeni je sluh epidemiološki i javnozdravstveni problem. Mutacija del35G u GJB2 genu najčešći je uzrok genetski uzrokovane gluhoće, a vizualizira se PCR-metodom. Uvođenje analize mutacije u dijagnostički algoritam oslabljenog sluha omogućuje brzu, preciznu i etiološku dijagnozu, a i informativno genetičko savjetovanje. Ispitivanjem hrvatske populacije iz Istarske i Primorsko-goranske županije, mutacija je nađena u 36% osoba oslabljenog sluha, slično do sada ispitivanim populacijama ustanovljena je incidencija mutacije u populaciji novorođenčadi od 1/1091 (95CI: 1/372 – 1/3205).Due to its frequency and the implications of early detection, hearing impairment has become an important epidemiological and public health care problem. Del35G/GJB2 mutation is the most common cause of genetic deafness, visualized by the PCR method. The mutation analysis has been successfully introduced in the diagnostics of deafness, and it enables fast, precise and etiologic diagnosis, as well as informative genetic counselling. The study of the Croatian population from the counties of Istria and Primorje-Gorski kotar revealed that the del35G mutation is involved in 36% of hearing impaired subjects; the incidence of the mutation in the population of newborns being 1/1091 (95CI: 1/372 – 1/3205)

Antioxidant Defenses Predict Long-Term Survival in a Passerine Bird

Normal and pathological processes entail the production of oxidative substances that can damage biological molecules and harm physiological functions. Organisms have evolved complex mechanisms of antioxidant defense, and any imbalance between oxidative challenge and antioxidant protection can depress fitness components and accelerate senescence. While the role of oxidative stress in pathogenesis and aging has been studied intensively in humans and model animal species under laboratory conditions, there is a dearth of knowledge on its role in shaping life-histories of animals under natural selection regimes. Yet, given the pervasive nature and likely fitness consequences of oxidative damage, it can be expected that the need to secure efficient antioxidant protection is powerful in molding the evolutionary ecology of animals. Here, we test whether overall antioxidant defense varies with age and predicts long-term survival, using a wild population of a migratory passerine bird, the barn swallow (Hirundo rustica), as a model.Plasma antioxidant capacity (AOC) of breeding individuals was measured using standard protocols and annual survival was monitored over five years (2006-2010) on a large sample of selection episodes. AOC did not covary with age in longitudinal analyses after discounting the effect of selection. AOC positively predicted annual survival independently of sex. Individuals were highly consistent in their relative levels of AOC, implying the existence of additive genetic variance and/or environmental (including early maternal) components consistently acting through their lives.Using longitudinal data we showed that high levels of antioxidant protection positively predict long-term survival in a wild animal population. Present results are therefore novel in disclosing a role for antioxidant protection in determining survival under natural conditions, strongly demanding for more longitudinal eco-physiological studies of life-histories in relation to oxidative stress in wild populations

Yolk carotenoids have sex-dependent effects on redox status and influence the resolution of growth trade-offs in yellow-legged gull chicks

Avian eggs are rich in carotenoids, which derive from maternal diet where they may be available in limiting amounts. Egg carotenoids may accomplish major roles in antioxidant protection or modulate physiological functions and growth, interfering with offspring redox status, potentially in a sex-dependent way. In this study of maternal effects in relation to sex and laying order of yellow-legged gull (Larus michahellis) chicks, we analyzed the consequences of increased yolk lutein concentration on plasma antioxidant capacity (AOC) and an index of early oxidative damage (reactive oxygen metabolites, ROM), till 9 days after hatching. To this end, for the first time we directly manipulated yolk lutein, thus avoiding any effect on other components of egg quality due to maternal supplementation before laying. Lutein did not increase AOC but increased ROM in males and in first-laid chicks. Hence, lutein did not act as an antioxidant and determined increased early oxidative damage, possibly because of upregulation of immune or other physiological functions, but these effects were sex-related and apparent in first-laid chicks with larger yolk lutein supply. ROM positively covaried with AOC, suggesting a trade-off between AOC and oxidative damage. Moreover, lutein injection altered the covariation between body size or immunity and AOC or ROM. Carotenoids may thus not be major antioxidants in birds and rather affect redox status by increasing oxidative damage in a sex-dependent way and interfere with the resolution of growth trade-offs. In the absence of sex-related allocation, maternal decisions on egg carotenoid concentration may depend on the balance between divergent effects on either sex. Copyright 2011, Oxford University Press.

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)