Social determinants of health and diabetic foot disease

Background Diabetic foot disease (DFD) is the leading cause of hospitalisation and lower extremity amputation (LEA) in people with diabetes. Many studies have established the relationship between DFD and clinical risk factors, such as peripheral neuropathy and peripheral arterial disease. Other studies have identified the relationship between diabetes and non-clinical risk factors termed social determinants of health (SDoH), such as socioeconomic status. However, it appears very few studies have investigated the relationship between DFD and SDoH. This paper aims to review the existing literature investigating the relationship between DFD and the SDoH factors socioeconomic status (SES), race and geographical remoteness (remoteness). Process Electronic databases (MEDLINE, CINAHL, and PubMed) were searched for studies reporting SES, race (including Aboriginal and Torres Strait Islander in Australia) and remoteness and their relationship to DFD and LEA. Exclusion criteria were studies conducted in developing countries and studies published prior to 2000. Findings Forty-eight studies met the inclusion criteria and were reviewed; 10 in Australia. Overall, 28 (58%) studies investigated LEA, 10 (21%) DFD, and 10 (21%) DFD and LEA as the DFD-related outcome. Thirty-six (75%) studies investigated the SDoH risk factor of race, 22 (46%) SES, and 20 (42%) remoteness. SES, race and remoteness were found to be individually associated with LEA and DFD in the majority of studies. Only four studies investigated interactions between SES, race and remoteness and DFD with contrasting findings. All four studies used only LEA as their investigated outcome. No Australian studies investigate the interaction of all three SDoH risk factors on DFD outcomes. Conclusions The SDoH risk factors of SES, race and GR appear to be individually associated with DFD. However, only few studies investigated the interaction of these three major SDoH risk factors and DFD outcomes with contrasting results. There is a clear gap in this area of DFD research and particularly in Australia. Until urgent future research is performed, current practice and policy does not adequately take into consideration the implication of SDoH on DFD.

Venous thromboembolism during pregnancy and the impact of thrombophilia in pregnancy complications

Venous thromboembolism (VTE) is the greatest single cause of maternal mortality in pregnant women in developed countries. Pregnancy is a hypercoagulable state and brings about an enhanced risk of deep venous thrombosis (DVT) in otherwise healthy women. Traditionally, unfractionated heparin (UFH) has been used for treatment of DVT during pregnancy. We showed in our observational study that low molecular weight heparin (LMWH) is as effective and safe as UFH in the treatment of DVT during pregnancy. Although DVT during pregnancy is often massive, increasing the risk of developing long-term consequences, namely post-thrombotic syndrome (PTS), only 11% of all patients had confirmed PTS 3 4 years after DVT. In our studies the prevalence of PTS was not dependent on treatment (UFH vs LMWH). Low molecular weight heparin is more easily administered, few laboratory controls are required and the hospital stay is shorter, factors that lower the costs of treatment. Cervical insufficiency is defined as repeated very preterm delivery during the second or early third trimester. Infection is a well-known risk factor of preterm delivery. We found overpresentation of thrombophilic mutations (FV Leiden, prothrombin G20210A)among 42 patients with cervical insufficiency compared with controls (OR 6.7, CI 2.7 18.4). Thus, thrombophilia might be a risk factor of cervical insufficiency possibly explained by interaction of coagulation and inflammation processes. The presence of antiphospholipid (aPL) antibodies increases the risk for recurrent miscarriage (RM). Annexins are proteins which all bind to anionic phospholipids (PLs) preventing clotting on vascular phospholipid surfaces. Plasma concentrations of circulating annexin IV and V were investigated in 77 pregnancies at the beginning of pregnancy among women with a history of RM, and in connection to their aPL antibody status. Control group consisted unselected pregnant patients (n=25) without history of adverse pregnancy outcome. Plasma levels of annexin V were significantly higher at the beginning (≤5th week) of pregnancy in women with aPL antibodies compared with those without aPL antibodies (P=0.03). Levels of circulating annexin V were also higher at the 6th (P= 0.01) and 8th week of pregnancy in subjects with aPL antibodies (P=0.01). Results support the hypothesis that aPL could displace annexin from anionic phospholipid surfaces of syncytiotrophoblasts (STBs) and may exert procoagulant activities on the surfaces of STBs Recurrent miscarriage (RM) has been suggested to be caused by mutations in genes coding for various coagulation factors resulting in thrombophilia. In the last study of my thesis were investigated the prevalence of thrombomodulin (TM) and endothelial protein C receptor polymorphism EPCR among 40 couples and six women suffering RM. This study showed that mutations in the TM or EPCR genes are not a major cause of RM in Finnish patients.

Gastrointestinal complications after kidney transplantation

The aim of the study was to evaluate gastrointestinal (GI) complications after kidney transplantation in the Finnish population. The adult patients included underwent kidney transplantation at Helsinki University Central Hospital in 1990-2000. Data on GI complications were collected from the Finnish Kidney Transplantation Registry, patient records and from questionnaires sent to patients. Helicobacter pylori IgG and IgA antibodies were measured from 500 patients before kidney transplantation and after a median 6.8-year follow up. Oesophagogastroduodenoscopy with biopsies was performed on 46 kidney transplantation patients suffering from gastroduodenal symptoms and 43 dyspeptic controls for studies of gastroduodenal cytomegalovirus (CMV) infection. Gallbladder ultrasound was performed on 304 patients after a median of 7.4 years post transplantation. Data from these 304 patients were also collected on serum lipids, body mass index and the use of statin medication. Severe GI complications occurred in 147 (10%) of 1515 kidney transplantations, 6% of them fatal after a median of 0.93 years. 51% of the complications occurred during the first post transplantation year, with highest incidence in gastroduodenal ulcers and complications of the colon. Patients with GI complications were older and had more delayed graft function and patients with polycystic kidney disease had more GI complications than the other patients. H.pylori seropositivity rate was 31% and this had no influence on graft or patient survival. 29% of the H.pylori seropositive patients seroreverted without eradication therapy. 74% of kidney transplantation patients had CMV specific matrix protein pp65 or delayed early protein p52 positive findings in the gastroduodenal mucosa, and 53% of the pp65 or p52 positive patients had gastroduodenal erosions without H.pylori findings. After the transplantation 165 (11%) patients developed gallstones. A biliary complication including 1 fatal cholecystitis developed in 15% of the patients with gallstones. 13 (0.9%) patients had pancreatitis. Colon perforations, 31% of them fatal, occurred in 16 (1%) patients. 13 (0.9%) developed a GI malignancy during the follow up. 2 H.pylori seropositive patients developed gastroduodenal malignancies during the follow up. In conclusion, severe GI complications usually occur early after kidney transplantation. Colon perforations are especially serious in kidney transplantation patients and colon diverticulosis and gallstones should be screened and treated before transplantation. When found, H.pylori infection should also be treated in these patients.

Primary polyestradiol phosphate versus orchiectomy for advanced prostate cancer : Studies on the efficacy, cardiovascular complications and prognostic factors

Paikallisesti levinnyttä (T3-4 M0) ja luustoon levinnyttä (T1-4 M1) eturauhassyöpää sairastaneet potilaat satunnaistettiin kirurgiseen kastraatioon (orkiektomia) tai lääkkeelliseen kastraatioon lihaksensisäisellä polyestradiolifosfaatilla (PEP) annoksella 240 mg/kk. Verrattiin hoitojen kliinistä tehoa sekä sydän- ja verisuonikomplikaatioita (SV-komplikaatioita). Verrattiin myös hoitoa edeltäviä plasman testosteroni (T) ja estradioli (E2) pitoisuuksia T3-4 M0 ja T1-4 M1 potilaiden välillä sekä selvitettiin potilaiden yleistilan vaikutusta näihin hormonitasoihin. Lopuksi luotiin T1-4 M1 potilaille eturauhassyövän aiheuttaman kuoleman ennusteellinen riskiluokittelu kolmeen riskiryhmään käyttämällä hoitoa edeltäviä ennustetekijöitä. Kliinisessä tehossa ei orkiektomian ja PEP-hoidon välillä todettu tilastollisesti merkitsevää eroa. Odotetusti T1-4 M1 potilaiden ennuste oli huonompi kuin T3-4 M0 potilaiden. T1-4 M1 potilailla ei ollut SV-kuolemissa hoitoryhmien välillä tilastollista eroa, mutta ei-tappavia SV-komplikaatioita oli PEP ryhmässä (5.9%) enemmän kuin orkiektomia ryhmässä (2.0%). T3-4 M0 potilailla PEP-hoitoon liittyi tilastollisesti merkitsevä SV-kuolleisuus riski orkiektomiaan verrattuna (p = 0.001). PEP ryhmässä 67% kuolemista oli akuutteja sydäninfarkteja. Tämä PEP hoitoon liittyvä sydäninfarktiriski (mukaan lukien myös ei-tappavat sydäninfarktit) oli merkitsevästi pienempi potilailla, joiden hoitoa edeltävä E2 taso oli vähintään 93 pmol/l (p = 0.022). E2 taso oli merkitsevästi matalampi T1-4 M1 potilailla (74.7 pmol/l) kuin T3-4 M0 potilailla (87.9 pmol/l), mutta vastaavaa eroa ei ollut T tasoissa. Sekä T3-4 M0 että T1-4 M1 potilailla yleistilan lasku osittain selitti yksilöllisen T ja E2 tasojen laskun. Eturauhassyövän aiheuttaman kuoleman riskiryhmäluokittelu (Rg) kolmeen ryhmään luotiin käyttämällä alkalista fosfataasia (AFOS), prostata spesifistä antigeenia (PSA), laskoa (La) ja potilaan ikää. Yksi riskipiste annettiin, jos AFOS > 180 U/l (tällä hetkellä käytössä olevalla menetelmällä AFOS > 83 U/l), PSA > 35 µg/l, La > 80 mm/h ja ikä < 60 vuotta. Lopuksi pisteet laskettiin yhteen. Muodostettiin seuraavat ryhmät: Rg-a (0 -1 riskipistettä), Rg-b (2 riskipistettä) ja Rg-c (3 – 4 riskipistettä). Eturauhassyövän aiheuttama kuoleman riski lisääntyi merkitsevästi siirryttäessä riskiryhmästä seuraavaan (p < 0.001). Rg-luokittelu oli kliinisesti käytännöllinen ja hyvä havaitsemaan huonon ennusteen potilaat.

Physical activity and diabetic complications in patients with type 1 diabetes

Type 1 diabetes is associated with the risk for late diabetic complications which are divided into microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular (cardiovascular disease, CVD) diseases. The risk for diabetic complication can be reduced by effective treatment, most importantly the glycaemic control. Glycaemia in type 1 diabetes is influenced by the interplay between insulin injections and lifestyle factors such as physical activity and diet. The effect of physical activity in patients with type 1 diabetes is not well known, however. The aim of this thesis was to investigate the physical activity and the physical fitness of patients with type 1 diabetes with special emphasis on glycaemic control and the diabetic complications. The patients included in the study were all part of the nationwide, multicenter Finnish Diabetic Nephropathy (FinnDiane) Study which aims to characterise genetic, clinical, and environmental factors that predispose to diabetic complications in patients with type 1 diabetes. In addition, subjects from the IDentification of EArly mechanisms in the pathogenesis of diabetic Late complications (IDEAL) Study were studied. Physical activity was assessed in the FinnDiane Study in 1945 patients by a validated questionnaire. Physical fitness was measured in the IDEAL Study by spiroergometry (cycle test with measurement of respiratory gases) in 86 young adults with type 1 diabetes and in 27 healthy controls. All patients underwent thorough clinical characterisation of their diabetic complication status. Four substudies were cross-sectional using baseline data and one study additionally used follow-up data. Physical activity, especially the intensity of activities, was reduced in patients affected by diabetic nephropathy, retinopathy, and CVD. Low physical activity was associated with poor glycaemic control, a finding most clear in women and evident also in patients with no signs of diabetic complications. Furthermore, low physical activity was associated with a higher HbA1c variability, which in turn was associated with the progression of renal disease and CVD during follow-up. A higher level of physical activity was also associated with better insulin sensitivity. The prevalence of the metabolic syndrome in type 1 diabetes was also lower the higher the physical activity. The aerobic physical fitness level of young adults with type 1 diabetes was reduced compared with healthy peers and in men an association between higher fitness level and lower HbA1c was observed. In patients with type 1 diabetes, a higher physical activity was associated with better glycaemic control and may thus be beneficial with respect to the prevention of diabetic complications.

Characterization of foot-and-mouth disease virus types Ο and Asia 1 RNA

Foot-and-mouth disease is an acute and highly contagious febrile disease affecting cloven-footed animals. Identification of the foot-and-mouth disease virus (FMDV), the causative agent of the disease, posed problems because of the occurrence of many types and subtypes of the virus. A molecular approach based on oligonucleotide mapping of FMDV RNA has been used for the identification and characterization of virus isolates obtained in a disease outbreak (King et al., 1981). One-dimensional oligonucleotide mapping was used for rapid analysis of FMDV RNA (LaTorre et al., 1982). FMDV types Ο and Asia 1 of Indian origin are being routinely used for vaccine production in India. This report presents the differences between FMDV types Ο and Asia 1 at molecular level based on one-dimensional oligonucleotide mapping of virus-induced poly (A) RNA.

Factor V Leiden as risk factor for pregnancy complications : Epidemiological study of Finnish women

Factor V Leiden (FV Leiden) is the most common inherited thrombophilia in Caucasians increasing the risk for venous thrombosis. Its prevalence in Finland is 2-3%. FV Leiden has also been associated with several pregnancy complications. However, the importance of FV Leiden as their risk factor is unclear. The aim of the study was to assess FV Leiden as a risk factor for pregnancy complications in which prothrombotic mechanisms may play a part. Specifically, the study aimed to assess the magnitude of the risk, if any, associated with FV Leiden for pregnancy-associated venous thrombosis, pre-eclampsia, unexplained stillbirth, and preterm birth. The study was conducted as a nested case-control study within a fixed cohort of 100,000 consecutive pregnant women in Finland. The study was approved by the ethics committee of the Finnish Red Cross Blood Service and by the Ministry of Social Affairs and Health. All participants gave written informed consent. Cases and controls were identified by using national registers. The diagnoses of the 100,000 women identified from the National Register of Blood Group and Blood Group Antibodies of Pregnant Women were obtained from the National Hospital Discharge Register. Participants gave blood samples for DNA tests and filled in questionnaires. The medical records of the participants were reviewed in 49 maternity hospitals in Finland. Genotyping was performed in the Finnish Genome Center. When evaluating pregnancy-associated venous thrombosis (34 cases, 641 controls), FV Leiden was associated with 11-fold risk (OR 11.6, 95% CI 3.6-33.6). When only analyzing women with first venous thrombosis, the risk was 6-fold (OR 5.8, 95% CI 1.6-21.8). The risk was increased by common risk factors, the risk being highest in women with FV Leiden and pre-pregnancy BMI over 30 kg/m2 (75-fold), and in women with FV Leiden and age over 35 years (60-fold). When evaluating pre-eclampsia (248 cases, 679 controls), FV Leiden was associated with a trend of increased risk (OR 1.7, 95% CI 0.8-3.9), but the association was not statistically significant. When evaluating unexplained stillbirth (44 cases, 776 controls), FV Leiden was associated with over 3-fold risk (OR 3.8, 95% CI 1.2-11.6). When evaluating preterm birth (324 cases, 752 controls), FV Leiden was associated with over 2-fold risk (OR 2.4, 95% CI 1.3-4.6). FV Leiden was especially associated with late preterm birth (32-36 weeks of gestation), but not with early preterm birth (< 32 weeks of gestation). The results of this large population-based study can be generalized to Finnish women with pregnancies continuing beyond first trimester, and may be applied to Caucasian women in populations with similar prevalence of FV Leiden and high standard prenatal care.

Characterization and immune response of a protein produced by a cDNA clone of foot and mouth disease virus, type Asia 1 63/72

A 0.9 kb double stranded cDNA of foot and mouth disease virus (FMDV) Type Asia 1, 63/72 was cloned in an expression vector, pUR222. A protein of 38 kd was produced by the clone which reacted with the antibodies raised against the virus. A 20 kd protein which may be derived from the 38 kd protein contained the antigenic epitopes of the protein VP1 of the virus. Injection of 10-20 micrograms of the partially purified 38 and 20 kd proteins or a lysate of cells containing 240 micrograms of the proteins elicited high titers of FMDV specific antibodies in guinea pigs and cattle respectively. Also, at these concentrations, the proteins protected 5 of 8 guinea pigs and 3 of 8 cattle when challenged with a virulent virus.

Expression of VP1 protein of serotype A and O of foot-and-mouth disease virus in transgenic sunnhemp plants and its immunogenicity for guinea pigs

Recently, transgenic plants expressing immunogenic proteins of foot-and-mouth disease virus (FMDV) have been used as oral or parenteral vaccines against foot-and-mouth disease (FMD). They exhibit advantages like cost effectiveness, absence of processing, thermostability, and easy oral application. FMDV VP1 protein of single serotype has been mostly used as immunogen. Here we report the development of a bivalent vaccine with tandem-linked VP1 proteins of two serotypes, A and O, present in transgenic forage crop Crotalaria juncea. The expression of the bivalent protein in the transgenic plants was confirmed by Western blot analysis. Guinea pig reacted to orally or parenterally applied vaccine by humoral as well as cell-mediated immune responses including serum antibodies and stimulated lymphocytes, respectively. The vaccine protected the animals against a challenge with the virus of serotype A as well as O. This is the first report on the development of a bivalent FMD vaccine using a forage crop.