Diabetes and peripheral arterial disease

Background: Diabetes mellitus increases the risk for peripheral arterial disease (PAD) early in life and the disease is likely to progress to advanced stages. Mechanisms responsible for premature PAD in diabetes are partly unknown. Leg ischaemia from PAD, together with other diabetic complications, is the key player in the pathway from ulceration to gangrene and infection, which ultimately results in major amputation. Infrainguinal bypass surgery (IBS) is carried out to restore leg perfusion and avoid amputations. Whether outcomes for this procedure are less favourable in patients with diabetes than in patients without diabetes is unclear. Aims: ‒To explore the impact of hyperglycaemia on outcome after IBS in patients with diabetes. ‒To assess amputation-free survival (AFS) after IBS for critical limb ischaemia. ‒To assess amputation-free survival (AFS) in patients with diabetes but without PAD during long term follow up. ‒To investigate if receptor for advanced glycation end products (RAGE) and advanced glycation end products (AGE) are increased in plasma and vein grafts in diabetes patients. ‒To investigate if the AGE-RAGE system predicts AFS and development of PAD, and if it is associated with AFS after IBS in patients with diabetes. Results: In Paper I, we demonstrated an association between hyperglycaemia the first 48 hours after IBS and increased risk for wound complications, graft occlusion and amputation or death during the first 3 months in 91 patients with diabetes. Patients in the highest quartile of glucose exposure had an odds ratio of 13‒14 in multivariate logistic regression. In Paper II, we performed a nationwide, population-based cohort study and compared postoperative AFS in patients with and without diabetes. The analysis included data for 1 840 patients from the Swedish Vascular Registry who, during 2001–2003, underwent their first unilateral, below-knee, IBS procedure for critical limb ischaemia. Of these patients, 742 had diabetes and 1,098 did not. Patients were followed up until the end of 2005. Overall, 446 and 558 patients with and without diabetes, respectively, had undergone ipsilateral amputation or died by the end of the follow-up period. Patients with diabetes had a shorter AFS than patients without diabetes (2.3 years, 95% CI 1.9–2.8 years versus 3.4 years, 95% CI 3.1–3.7 years). The hazard ratio and incidence for ipsilateral amputation or death in patients with diabetes, adjusted for age, sex, smoking and other confounding variables, was 1.46 (95% CI 1.26–1.69) and 30.2 events per 100 person-years respectively. The incidence of amputation or death was 2.8 per 100 person-years, (95% CI 2.0 to 3.7) in the cohort of patients with type 2 diabetes who were free from PAD at start of follow up. In Paper III and IV we showed that S100A12, a ligand to RAGE, is associated with AFS after IBS in patients with (n=38) and without (n=30) diabetes, and with AFS as well as development of PAD in a prospective longitudinal (10-year) population-based cohort (n=146) of patients with type 2 diabetes, free from signs of PAD at inclusion. Presence of AGE, RAGE and S100A12 were demonstrated in saphenous vein tissue with no difference between patients with and without diabetes. Conclusions: Postoperative hyperglycaemia is associated with unfavourable outcome after IBS in patients with diabetes. Diabetes is associated with lower AFS after IBS for critical limb ischaemia. Plasma levels of S100A12 and RAGE components are elevated in PAD disease and markers of RAGE and its ligands are found in vein tissue used for bypass. This is consistent with a role for S100A12 in PAD complications by activation of the RAGE system. Higher plasma levels of S100A12 and the combined effect of RAGE components seem to be associated with AFS in patients with diabetes. Further study is needed to find methods of reducing this excess risk and prolonging AFS

Computer Controlled Testing System for Electrical Safety Measurements

Työssä suunniteltiin ja toteutettiin GE Healthcare Finland Oy:n käyttöön uusi testausjärjestelmä, jolla voidaan tehdä sähköturvallisuusmittaukset standardien IEC-60601, EN-50191 ja EN-50116 mukaisesti ja niiden vaatimassa ympäristössä. Vanhaan järjestelmään verrattuna uusi testausjärjestelmä on parempi siinä, että kaikki sähköturvallisuustestaus tehdään yhdellä laitteella. Lisäksi uusi järjestelmä on automaattinen testattavien tuotteiden määräämissä rajoissa. Myös ohjelmistoa tehtiin yhtenäisemmäksi testausympäristön osalta. Testauksissa käytettävät asetukset tehtiin jälkeenpäin muokattaviksi. Testauslaitteeksi valittiin Associated Research Inc. Omnia 8106. Automaattisuus mahdollistettiin saman valmistajan SC6540 matriisiskannerilla. Ulkoiseksi teholähteeksi valittiin California Instrumentsin 801RP. Suunnittelu toteutettiin ohjelmiston käytettävyyttä silmällä pitäen, ja testausjännitteistä, testausvirroista, rasitusajoista ym. tehtiin muokattavissa olevia. Testausympäristöksi valittiin muilla GE Healthcaren testausosastoilla käytössä oleva National Instrumentsin testijonosekvensseri, TestStand. Testausmetodit toteutettiin LabVIEW ohjelmointikielellä. Järjestelmään tehtiin myös editori, jolla pystytään ylläpitämään laitteille tehtäviä testejä ja niiden asetuksia, tarkastelemaan raportteja, ylläpitämään käyttöoikeuksia ja muokkaamaan laitekohtaisia asetuksia. Tuloksena saatiin testiajojen perusteella toistettavasti testejä tekevä ja kattava testausjärjestelmä, jolla pystytään tekemään testejä nopeammin vanhaan järjestelmään verrattuna järjestelmän automaattisuuden ansiosta. Tyypillisesti testattavan laitteen kytkeminen järjestelmään kestää noin 30 s ja testaaminen noin 2 min. Uudesta järjestelmästä saatiin lisäksi monipuolisempi ja tarkempi uusien testityyppien ja tarkemman testauslaitteen ansiosta. Järjestelmä mittaa dielektrisyyden lujuuden testit 2,1 % epävarmuudella, vuotovirtatestit 1,7 % epävarmuudella ja suojamaadoituksen impedanssin testit 4,0 % epävarmuudella.In this master's thesis, a test system was designed and implemented. The system is able to execute electrical safety tests according to the requirements of IEC-60601, EN-50191 and EN-50116 standards for test environment and methods. System will be used by GE Healthcare Finland. As compared to the previous testing system, the new system is better, because it executes all electrical safety tests with one testing device. Besides, the system is as automatic as products allow. The Software was also designed to be more integrated concerning the interface of the software. Settings of the tests are configurable afterwards. Associated Research Inc. Omnia 8106 was chosen to be the testing device and SC6540 matrix scanner from the same manufacturer automates testing. California Instruments 801RP was chosen to be the external power supply of the system. The software was designed for usability. Testing voltages, currents and stress times were designed to be configurable. National Instruments test sequencer, TestStand was chosen to be the interface for testing. It is also used in other testing sites of GE Healthcare. Testing methods were implemented with the LabVIEW programming language. An editor, which can be used to maintain tests and specifications of the devices, to view testing reports, to maintain access rights and to configure device-specific settings, was also implemented for the testing system. According to beta testing, the system was reliable and inclusive. It can be used to execute tests faster than the previous system. Typically connecting of a unit to the system takes approximately 30 s of time and testing of a unit approximately 2 min of time. The new system was more versatile and accurate, because of new test types and more accurate testing device. The system measures dielectric strength tests with uncertainty of 2,1 %, leakage current tests with uncertainty of 1,7 % and protective earth tests with uncertainty of 4,0 %

Blogien kaupallistuminen : Kinuskikissa-sivuston sisällönanalyysi

Siirretty Doriast

Oncolytic Adenovirus Type 3 Coding for CD40L Facilitates Dendritic Cell Therapy of Prostate Cancer in Humanized Mice and Patient Samples

Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.Peer reviewe

Integrating isotopes and documentary evidence : dietary patterns in a late medieval and early modern mining community, Sweden

We would like to thank the Archaeological Research Laboratory, Stockholm University, Sweden and the Tandem Laboratory (Ångström Laboratory), Uppsala University, Sweden, for undertaking the analyses of stable nitrogen and carbon isotopes in both human and animal collagen samples. Also, thanks to Elin Ahlin Sundman for providing the δ13C and δ15N values for animal references from Västerås. This research (Bäckström’s PhD employment at Lund University, Sweden) was supported by the Berit Wallenberg Foundation (BWS 2010.0176) and Jakob and Johan Söderberg’s foundation. The ‘Sala project’ (excavations and analyses) has been funded by Riksens Clenodium, Jernkontoret, Birgit and Gad Rausing’s Foundation, SAU’s Research Foundation, the Royal Physiographic Society of Lund, Berit Wallenbergs Foundation, Åke Wibergs Foundation, Lars Hiertas Memory, Helge Ax:son Johnson’s Foundation and The Royal Swedish Academy of Sciences.Peer reviewedPublisher PD

Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial: A survival prediction model to facilitate clinical decision making

BackgroundAn intention-to-treat analysis of the Bypass versus Angioplasty in Severe Ischaemia of the Leg (BASIL) trial showed that in patients with severe lower limb ischemia (SLI) due to infrainguinal disease who survived for 2 years after intervention, initial randomization to a bypass surgery (BSX)-first vs balloon angioplasty (BAP)-first revascularization strategy was associated with improvements in subsequent overall survival (OS) and amputation-free survival (AFS) of about 7 and 6 months, respectively. This study explored the value of baseline factors to estimate the likelihood of survival to 2 years for the trial cohort (Cox model) and for individual BASIL trial patients (Weibull model) as an aid to clinical decision making.MethodsOf 452 patients presenting to 27 United Kingdom hospitals, 228 were randomly assigned to a BSX-first and 224 to a BAP-first revascularization strategy. Patients were monitored for at least 3 years. Baseline factors affecting the survival of the entire cohort were examined with a multivariate Cox model. The chances of survival at 1 and 2 years for patients with given baseline characteristics were estimated with a Weibull parametric model.ResultsAt the end of follow-up, 172 patients (38%) were alive without major limb amputation of the trial leg, and 202 (45%) were alive. Baseline factors that were significant in the Cox model were BASIL randomization stratification group, below knee Bollinger angiogram score, body mass index, age, diabetes, creatinine level, and smoking status. Using these factors to define five equally sized groups, we identified patients with 2-year survival rates of 50% to 90%. The factors that contributed to the Weibull predictive model were age, presence of tissue loss, serum creatinine, number of ankle pressure measurements detectable, maximum ankle pressure measured, a history of myocardial infarction or angina, a history of stroke or transient ischemia attack, below knee Bollinger angiogram score, body mass index, and smoking status.ConclusionsPatients in the BASIL trial were at high risk of amputation and death regardless of revascularization strategy. However, baseline factors can be used to stratify those risks. Furthermore, within a parametric Weibull model, certain of these factors can be used to help predict outcomes for individuals. It may thus be possible to define the clinical and anatomic (angiographic) characteristics of SLI patients who are likely—and not likely—to live for >2 years after intervention. Used appropriately in the context of the BASIL trial outcomes, this may aid clinical decision making regarding a BSX- or BAP-first revascularization strategy in SLI patients like those randomized in BASIL

Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Background: Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods: ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings: Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation: Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding: UK Medical Research Council and Health Technology Assessment Programme