Cardioprotective and Antifibrotic Effects of Low-Dose Renin-Angiotensin-Aldosterone System Inhibitors in Type 1 Diabetic Rat Model.

Diabetic cardiovascular complications are associated with up to 50% mortality, and current therapies are not effective enough. Renin-angiotensin-aldosterone system inhibitors (RAASis) are the standard of care for diabetic patients with hypertension and albuminuria. Based on our previous studies reporting the renoprotective effects of low-dose RAASis, here, we hypothesized that low-dose RAASi treatment has cardioprotective and antifibrotic benefits in type 1 diabetes mellitus (T1DM). After five weeks of T1DM, adult male Wistar rats received low doses of ramipril, losartan, or eplerenone for two weeks. Heart rate, blood pressure, and pulse wave velocity (PWV) were recorded. Aortic intima-media thickness (IMT), collagen accumulation, and myocardial fibrosis were assessed. All RAASis reduced PWV elevation, prevented the progression of myocardial fibrosis, and normalized B-type natriuretic peptide, troponin I, and fibroblast growth factor 23 levels without affecting blood pressure. Interestingly, only eplerenone reversed the decline in Klotho levels and reduced IMT and fibrosis in the media of the aorta. Our comparative analysis suggests that mineralocorticoid receptor antagonists, particularly eplerenone, may offer superior efficacy in halting both the arterial and the myocardial injuries in T1DM compared to angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor blockers.

Differences in the associations between psychoactive substance use and alexithymia: A series of Meta-analyses.

The present meta-analytic study examined the association between alexithymia and psychoactive substance use. Studies published from 1988 to August 20, 2022 were identified by a systematic search and 168 eligible studies were included in five meta-analyses. Results showed that (1) the correlation between substance use and alexithymia is small but significant (r = 0.177); (2) substance users have substantially higher alexithymia than nonusers (g = 0.545); (3) alexithymic participants have significantly but slightly higher levels of substance use than non-alexithymics (g = 0.242); (4) substance users are significantly but only slightly more likely to be alexithymic than nonusers (OR = 2.392); and (5) alexithymic individuals are not more likely to be substance users than non-alexithymics. Larger effects were observed among samples diagnosed with substance use disorder (SUD), and the use of depressants, alcohol, opiates, and illicit stimulants had stronger relation to alexithymia. We found a tendency for a larger association with problematic use as compared to other indicators (e.g., frequency and duration) of substance use. Among the components of alexithymia, difficulties in identifying feelings has the strongest association with substance use. Our findings support clinical practice by suggesting the improvement of emotion regulation in SUD.

SGLT2 inhibitor dapagliflozin prevents atherosclerotic and cardiac complications in experimental type 1 diabetes.

INTRODUCTION: Cardiovascular disease (CVD) is two to five times more prevalent in diabetic patients and is the leading cause of death. Therefore, identification of novel therapeutic strategies that reduce the risk of CVD is a research priority. Clinical trials showed that reduction in the relative risk of heart failure by sodium-glucose cotransporter 2 inhibitors (SGLT2i) are partly beyond their glucose lowering effects, however, the molecular mechanisms are still elusive. Here we investigated the role of SGLT2i dapagliflozin (DAPA) in the prevention of diabetes-induced cardiovascular complications. METHODS: Type 1 diabetes was induced with streptozotocin (65 mg/bwkg, ip.) in adult, male Wistar rats. Following the onset of diabetes rats were treated for six weeks with DAPA (1 mg/bwkg/day, po.). RESULTS: DAPA decreased blood glucose levels (D: 37±2.7 vs. D+DAPA: 18±5.6 mmol/L; p<0.05) and prevented metabolic decline. Aortic intima-media thickening was mitigated by DAPA. DAPA abolished cardiac hypertrophy, and myocardial damage. Cardiac inflammation and fibrosis were also moderated after DAPA treatment. CONCLUSIONS: These data support the preventive and protective role of SGLT2i in diabetes-associated cardiovascular disease. SGLT2i may provide novel therapeutic strategy to hinder the development of cardiovascular diseases in type 1 diabetes, thereby improve the outcomes.

Effects of alpha-lipoic acid treatment on serum progranulin levels and inflammatory markers in diabetic neuropathy.

OBJECTIVES: Progranulin (PGRN) is a secreted growth factor that helps to regulate neuronal survival by blocking tumor necrosis factor-alpha (TNFα) receptors. The antioxidant alpha-lipoic acid (ALA) is used in diabetic neuropathy to improve nerve conduction and relieve neuropathic pain, but its effects on PGRN levels have not yet been elucidated. METHODS: In this prospective study, 54 patients with type 2 diabetes and peripheral neuropathy received 600 mg of ALA daily for 6 months. Twenty-four patients with diabetes without neuropathy were also included in the study. Serum PGRN and TNFα levels were determined using enzyme-linked immunosorbent assays. In addition, current perception threshold (CPT) testing was used to assess sensory neuropathy. RESULTS: After ALA treatment, serum PGRN levels were significantly increased and CPT values were significantly improved. Furthermore, there were significant positive correlations among TNFα, ICAM-1, and PGRN levels both before and after ALA treatment. A significant negative correlation was observed between the improvements in CPT and the PGRN levels. Furthermore, ICAM-1 levels were an independent predictor of PGRN levels. CONCLUSIONS: Changes in serum PGRN levels indicate that ALA treatment may have beneficial effects on endothelial function and neuronal inflammation.

Lyophilization and homogenization of biological samples improves reproducibility and reduces standard deviation in molecular biology techniques.

Lyophilization is a cost-effective method for biological specimen preservation but detailed tissue-specific reference protocols are still lacking. Moreover, data are limited on the long-term stability of proteins and nucleic acids in lyophilized samples.Here, we offer lyophilization protocols for various rat and mouse tissues (kidney, heart, liver, lung, aorta, and skin) coupled with technical hints for optimal sample preparation. We demonstrate that lyophilized samples stored at 4 °C for 20 months can yield protein and RNA of similar quantity and quality to -80 °C storage, while phosphorylated proteins are preserved as well. Freeze-dried and subsequently pulverized samples can provide more consistent, more reliable data especially when investigating focal injuries, such as fibrosis. We developed a protocol for the concentration of biological solutions and achieved 20-times concentration in human peritoneal dialysis effluent solution which enables the previously unattainable detection of proteins in these samples. We established a method for water removal as well as accurate water content measurement of fecal samples, which can be valuable for gut metabolome analysis.Taken together, lyophilization is a valuable tool for the preservation of biological samples with many advantages. We aim to draw attention to the wide range of possibilities offered by freeze drying in pre-clinical or basic research.

The Role of Genetic Analysis in Correct Diagnosis of Eosinophilic Variant of Chromophobe Renal Cell Carcinoma.

BACKGROUND/AIM: It has been suggested that eosinophilic variant of chromophobe renal cell carcinoma (chRCC) with low chromosome number or lack of genomic alteration has an excellent prognosis in comparison to classic chRCC. The aim of our study was to analyse the phenotypical variations of 77 chRCCs, including 7 eosinophilic ones, each diagnosed unequivocally by genetic means. MATERIALS AND METHODS: DNA isolated from chRCCs was subjected to array comparative genomic hybridisation (CGH) for establishing the chromosome alteration. Original histological slides were evaluated for cellular phenotype and growth pattern and compared to the genetic alterations. RESULTS: Loss of the entire chromosome 1, 2, 6, 10, 13, 17 and 21 occurred in 95%, 94%, 86% 90% 82% 90% and 66% of the cases, respectively. The number of chromosome alterations in eosinophilic forms of chRCC corresponded to those found in classic chRCC with pale-reticular cytoplasm or mixed cellular characteristics. Three of seven eosinophilic variants with loss of 4, 10 and 11 chromosomes showed metastasis at the time of diagnosis whereas only 3 metastatic tumors were noticed among the 70 classic chRCC. We did not find discriminating difference in number of chromosome alteration between classic and eosinophilic forms of chRCC. CONCLUSION: Eosinophilic chRCC has a more aggressive biology than the classic form. To avoid diagnostic pitfall of eosinophilic renal cell tumors with uncertain diagnosis, a genetic analysis should be carried out.

Diabetic neuropathy and other diabetic complications at the Diabetic Neuropathy Center of the University of Debrecen / A diabeteses neuropathia és egyéb szövodmények elofordulása a Debreceni Egyetem Diabeteses Neuropathia Centrumában

INTRODUCTION: The prevalence of diabetes mellitus is significantly increasing worldwide. Distal sensorimotor neuropathy (DSPN) is the most common and the earliest detectable microvascular complication. Due to its diverse clinical appearance and atypical symptoms, DSPN is often recognized in an advanced stage. AIM AND METHOD: In our study, the data of 431 patients who were examined using the Neurometer® between 2011 and 2018 at the Diabetic Neuropathy Center of the University of Debrecen were processed and the correlations between cardiovascular and microvascular complications, laboratory parameters and the severity of DSPN were investigated. RESULTS: The average age of patients was 63.4 years, 62% of them were women, and 92% had type 2 diabetes mellitus. The average duration of diabetes was 13.7 years. Cardiovascular disease (CVD) was diagnosed in 42% of the patients. The incidence of retinopathy was 12%, persistent microalbuminuria was 16%. Despite DSNP complaints, neuronal damage could not be detected in 19%; in the examined patients 49% had mild, 19% moderate and 13% severe neuropathy. Diabetes-related neurological damage was more serious in the presence of both diabetic retinopathy (p<0.001) and microalbuminuria (p<0.001). The incidence of these microvascular complications and the severity of DSPN showed a significant positive correlation (p<0.001). There was no correlation between the severity of peripheral neuropathy and the development of CVD, and we did not find any correlations between the severity of DSPN and CVD. CONCLUSION: Based on our investigation, correlation between the progression of diabetic neuropathy and cardiovascular complications was not found, although the progression of diabetic neuropathy indicated the development of other microvascular diseases. Peripheral neurological examination using the Neurometer® is appropriate for controlling the DSPN status and the establishment of the severity of neuropathy determines the quality of life in diabetic patients. Among these patients, the risk of CVD can be assessed by Ewing's test for autonomic nervous system function. Orv Hetil. 2020; 161(30): 1243-1251.

Antidepressant effect in diabetes-associated depression: A novel potential of RAAS inhibition.

The incidence of depression doubles in diabetic patients and is associated with poor outcomes. Studies indicate that renin-angiotensin-aldosterone system inhibitors (RAASi) might relieve depression, however the mechanism of action is not well understood. We recently showed that angiotensin receptor blockers have antidepressant effects in experimental diabetes comorbid depression. Here we investigated whether all types of RAASi exhibit antidepressant and neuroprotective properties. Diabetes was induced by streptozotocin in adult male Wistar rats. After 5 weeks of diabetes, rats were treated per os with non-pressor doses of enalapril, ramipril, spironolactone or eplerenone for 2 weeks. Behavior was evaluated using forced swim test and open field test. Inflammatory response and brain-derived neurotrophic factor (BDNF) signaling were investigated in the hippocampus. Both ACEi and MR antagonists reversed diabetes-induced behavioral despair confirming their antidepressant-like effect. This may occur via alterations in hippocampal cytokine-mediated inflammatory response. Repressed BDNF production was restored by RAASi. Both ACEi and MR antagonists facilitated the BDNF-tropomyosin receptor kinase B-cAMP response element-binding protein signaling pathway as part of their neuroprotective effect. These data highlight the important benefits of ACEi and MR antagonists in the treatment of diabetes-associated depressive symptoms. Our novel findings support the link between diabetes comorbid depression, inflammation and repressed BDNF signaling. RAASi could provide new therapeutic options to improve the outcomes of both disorders.

FOXI1 Immunohistochemistry Differentiates Benign Renal Oncocytoma from Malignant Chromophobe Renal Cell Carcinoma.

BACKGROUND/AIM: Renal oncocytoma (RO) and chromophobe renal cell carcinoma (chRCC) are suggested to develop from α- and ß-intercalated (IC) cells of the collecting duct expressing solute carrier family 4 member 1 (SLC4A1) and SLC26A4 under control of forkhead box 1 (FOXI1) transcription factor. The aim of this study was to clarify the possible cellular origin and of RO and chRCC. MATERIALS AND METHODS: Immunohistochemistry for aquaporin 2 (AQP2), FOXI1, SLC4A1 and SLC16A4 was applied to distinct types of renal cell tumors. RESULTS: Nuclear FOXI1 staining occurred in 96% of 83 ROs, in 3% of 90 chRCCs and none of the other tumor types. The α-IC cell marker SLC4A1 was seen in 60% of RO and 11% of chRCC, whereas staining for the ß-IC cell marker SLC26A4 was negative in all but one tumor. CONCLUSION: Although the origin of RO remains unclear, our findings suggest that FOXI1 immunohistochemistry is useful in differential diagnosis of RO from chRCC with overlapping histology.

RAAS inhibitors directly reduce diabetes-induced renal fibrosis via growth factor inhibition.

KEY POINTS: Increased activation of the renin-angiotensin-aldosterone system (RAAS) and elevated growth factor production are of crucial importance in the development of renal fibrosis leading to diabetic kidney disease. The aim of this study was to provide evidence for the antifibrotic potential of RAAS inhibitor (RAASi) treatment and to explore the exact mechanism of this protective effect. We found that RAASi ameliorate diabetes-induced renal interstitial fibrosis and decrease profibrotic growth factor production. RAASi prevents fibrosis by acting directly on proximal tubular cells, and inhibits hyperglycaemia-induced growth factor production and thereby fibroblast activation. These results suggest a novel therapeutic indication and potential of RAASi in the treatment of renal fibrosis. ABSTRACT: In diabetic kidney disease (DKD) increased activation of renin-angiotensin-aldosterone system (RAAS) contributes to renal fibrosis. Although RAAS inhibitors (RAASi) are the gold standard therapy in DKD, the mechanism of their antifibrotic effect is not yet clarified. Here we tested the antifibrotic and renoprotective action of RAASi in a rat model of streptozotocin-induced DKD. In vitro studies on proximal tubular cells and renal fibroblasts were also performed to further clarify the signal transduction pathways that are directly altered by hyperglycaemia. After 5 weeks of diabetes, male Wistar rats were treated for two more weeks per os with the RAASi ramipril, losartan, spironolactone or eplerenone. Proximal tubular cells were cultured in normal or high glucose (HG) medium and treated with RAASi. Platelet-derived growth factor (PDGF) or connective tissue growth factor (CTGF/CCN2)-induced renal fibroblasts were also treated with various RAASi. In diabetic rats, reduced renal function and interstitial fibrosis were ameliorated and elevated renal profibrotic factors (TGFß1, PDGF, CTGF/CCN2, MMP2, TIMP1) and alpha-smooth muscle actin (αSMA) levels were decreased by RAASi. HG increased growth factor production of HK-2 cells, which in turn induced activation and αSMA production of fibroblasts. RAASi decreased tubular PDGF and CTGF expression and reduced production of extracellular matrix (ECM) components in fibroblasts. In proximal tubular cells, hyperglycaemia-induced growth factor production increased renal fibroblast transformation, contributing to the development of fibrosis. RAASi, even in non-antihypertensive doses, decreased the production of profibrotic factors and directly prevented fibroblast activation. All these findings suggest a novel therapeutic role for RAASi in the treatment of renal fibrosis.

Reduced GLP-1 response to a meal is associated with the CTLA4 rs3087243 G/G genotype.

Although insulitis is the characteristic main feature of type 1 diabetes mellitus (T1DM), many aspects of ß cell loss still remain elusive. Immune dysregulation and alterations in the dipeptidyl-peptidase-4-incretin system might have a role in disease development, but their connection is poorly understood. We assessed the associations of a few selected, immunologically relevant single nucleotide gene variants with the DPP-4-incretin system in individuals with T1DM and in healthy controls. Prandial plasma (total, active) GLP-1 levels, serum DPP-4 activity, CD25 and CTLA-4 expression of T cells and DPP4 rs6741949, CTLA4 rs3087243, CD25 rs61839660 and PTPN2 rs2476601 SNPs were assessed in 33 T1DM patients and 34 age-, gender-, BMI-matched non-diabetic controls without a family history of T1DM. CTLA-4 expression was lower in the Foxp3+CD25+ regulatory T cells from individuals homozygous for the CTLA4 rs3087243-G variant compared to those who carry an A allele. Prandial plasma total GLP-1 levels 45 min after a standardized meal were reduced in individuals homozygous for the CTLA4 rs3087243 G major allele compared to A allele carriers both in the entire study population (with statistical power over 90%) and within the T1DM group. Here we report for the first time a reduced total prandial GLP-1 plasma concentration in individuals with the CTLA4 rs3087243 G/G genotype. One may speculate that immune response-related L cell damage might possibly explain this novel association.

An unexpected, mild phenotype of glucocorticoid resistance associated with glucocorticoid receptor gene mutation case report and review of the literature.

BACKGROUND: Glucocorticoid resistance is a rare, sporadic or familial condition caused by mutation of the gene encoding the glucocorticoid receptor (GR). Clinically it is characterized by symptoms developed due to local, tissue-specific, or generalized partial insensitivity to glucocorticoids. CASE PRESENTATION: A 31-year-old woman was evaluated because of infertility at the Endocrine Unit of the 2nd Department of Medicine, Semmelweis University. During her laboratory investigations, elevated serum and salivary cortisol were observed which failed to be suppressed after administration of 1 mg dexamethasone. 24 h urinary cortisol was increased, but a normal midnight serum cortisol was detected suggesting a maintained circadian rhythm. Plasma dehydroepiandrosterone-sulfate and androstendione levels were also elevated. Repeated plasma ACTH measurements indicated slightly elevated or normal values. Bone mineral density was normal. All laboratory results confirmed the diagnosis of glucocorticoid resistance. Genetic counseling followed by Sanger sequencing of the coding region of the gene encoding human glucocorticoid receptor was performed and a missense mutation (Arg714Gln, R714Q) in a heterozygous form was detected. Following family screening, the same mutation was found in her clinically-healthy 35-year-old sister who had no fertility problems.This variant was not detected in more than 60 patients and controls tested either for glucocorticoid resistance or Cushing's syndrome in our Laboratory and it was absent in Exome Variant Server, HumanGene Mutation Database and ExAC databases. CONCLUSIONS: Our case fulfils the diagnostic criteria of glucocorticoid resistance, also named Chrousos syndrome. The glucocorticoid receptor gene mutation detected in our patient has been already reported in a 2-year-old child with hypoglycaemia, hypokalaemia, hypertension and premature puberty. These distinct phenotypes may suggest that other factors may modify the functional consequences of the R714Q variant of GR.

"One program that could improve health in this neighbourhood is ____?" using concept mapping to engage communities as part of a health and human services needs assessment.

BACKGROUND: This paper presents the findings of a rapid needs assessment conducted at the request of the local health authority responsible for health care services, the Toronto Central Local Health Integration Network (Ontario, Canada), to inform health and social service planning. METHODS: We utilized concept mapping methodology to facilitate engagement with diverse stakeholders-more than 300 community members and service providers-with a focus on hard to reach populations. Key informant interviews with service providers were used to augment findings. RESULTS: Participants identified 48 unique services or service approaches they believed would improve the health of residents in the area, including those addressing health care, mental health and addictions, youth, families, people experiencing homelessness, seniors, general social services, and services targeting specific populations. While service providers consistently identified a critical need for mental health and addiction services, community members placed greater importance on the social determinants of health including access to housing, job placement supports and training and service accessibility. Both groups agreed that services and programs for seniors and people experiencing homelessness would be highly important. CONCLUSION: Our study provides a unique example of using concept mapping as a tool to aid a rapid service gap analysis and community engagement in a metropolitan area. The findings also reinforce the importance of working cross-sectorally, using a Health in All Policies approach when planning services for underserved populations.

Connections between unemployment insurance, poverty and health: a systematic review.

Background: Since the global economic crisis in 2007, unemployment rates have escalated in most European and North American countries. Unemployment protection policies, particularly the unemployment insurance (UI) system, have become a weighty issue for many modern welfare states. Decades of research have established concrete findings on the adverse impacts of unemployment on poverty- and health-related outcomes. This provided a foundation for further exploration into the potential protective effects of UI in offsetting these adverse outcomes. Methods: We developed a systematic review protocol in four stages (literature search, study selection, data extraction and quality appraisal) to ensure a rigorous data collection and inter-rated reliability. We examined the full body of empirical research published between 2000 and 2013 on the pathways by which UI impacts poverty and health. Results: Out of 2233 primary studies identified, a total of 12 met our inclusion criteria. The selected studies assessed poverty-related outcomes (absolute/relative poverty and material hardship) or one or more health-related outcomes (health behaviors, self-rated health, well-being and mental health). Across various UI systems, jurisdictions from high income countries, and study designs, we found good support for our conceptual framework, by which UI attenuates the effect of unemployment on both poverty and health, with a few exceptions. Conclusion: Whether UI impacts differ by age and region might be explored further in future research. The complex mediating relationship between unemployment, UI, poverty and health should further be assessed in light of economic and historical contexts. This could inform decision-making processes during future periods of economic recession.

[The role of oxidative stress in the development of diabetic neuropathy]. / Az oxidatív stressz szerepe a diabeteses neuropathia kialakulásában.

Diabetic neuropathy may be one of the most common and severe complications of diabetes mellitus. Oxidative stress plays a pivotal role in the development of microvascular complications of diabetes. The majority of related pathways like polyol and hexosamine, advanced glycation end products, poly-ADP-ribose polymerase, and protein kinase-C all originated from initial oxidative stress. In this review, the authors present the current oxidative stress hypothesis in diabetes mellitus and summarize the pathophysiological mechanisms of diabetic neuropathy associated with increased oxidative stress. The development of modern medicines to treat diabetic neuropathy needs intensive long-term comparative trials in the future. Orv. Hetil., 2016, 157(49), 1939-1946.

Role of O-linked N-acetylglucosamine modification in diabetic nephropathy.

Increased O-linked ß-N-acetylglucosamine glycosylation (O-GlcNAcylation) is a known contributor to diabetes; however, its relevance in diabetic nephropathy (DN) is poorly elucidated. Here, we studied the process and enzymes of O-GlcNAcylation with a special emphasis on Akt-endothelial nitric oxide synthase (eNOS) and heat shock protein (HSP)72 signaling. Since tubular injury is the prominent site of DN, the effect of hyperglycemia was first measured in proximal tubular (HK2) cells cultured in high glucose. In vivo O-GlcNAcylation and protein levels of O-GlcNAc transferase (OGT), O-GlcNAcase (OGA), phosphorylated (p)Akt/Akt, peNOS/eNOS, and HSP72 were assessed in the kidney cortex of streptozotocin-induced diabetic rats. The effects of various renin-angiotensin-aldosterone system (RAAS) inhibitors were also evaluated. In proximal tubular cells, hyperglycemia-induced OGT expression led to increased O-GlcNAcylation, which was followed by a compensatory increase of OGA. In parallel, peNOS and pAkt levels decreased, whereas HSP72 increased. In diabetic rats, elevated O-GlcNAcylation was accompanied by decreased OGT and OGA. RAAS inhibitors ameliorated diabetes-induced kidney damage and prevented the elevation of O-GlcNAcylation and the decrement of pAkt, peNOS, and HSP72. In conclusion, hyperglycemia-induced elevation of O-GlcNAcylation contributes to the progression of DN via inhibition of Akt/eNOS phosphorylation and HSP72 induction. RAAS blockers successfully inhibit this process, suggesting a novel pathomechanism of their renoprotective action in the treatment of DN.

Using Win-Win Strategies to Implement Health in All Policies: A Cross-Case Analysis.

BACKGROUND: In spite of increasing research into intersections of public policy and health, little evidence shows how policy processes impact the implementation of Health in All Policies (HiAP) initiatives. Our research sought to understand how and why strategies for engaging partners from diverse policy sectors in the implementation of HiAP succeed or fail in order to uncover the underlying social mechanisms contributing to sustainable implementation of HiAP. METHODS: In this explanatory multiple case study, we analyzed grey and peer-review literature and key informant interviews to identify mechanisms leading to implementation successes and failures in relation to different strategies for engagement across three case studies (Sweden, Quebec and South Australia), after accounting for the role of different contextual conditions. FINDINGS: Our results yielded no support for the use of awareness-raising or directive strategies as standalone approaches for engaging partners to implement HiAP. However, we found strong evidence that mechanisms related to "win-win" strategies facilitated implementation by increasing perceived acceptability (or buy-in) and feasibility of HiAP implementation across sectors. Win-win strategies were facilitated by mechanisms related to several activities, including: the development of a shared language to facilitate communication between actors from different sectors; integrating health into other policy agendas (eg., sustainability) and use of dual outcomes to appeal to the interests of diverse policy sectors; use of scientific evidence to demonstrate the effectiveness of HiAP; and using health impact assessment to make policy coordination for public health outcomes more feasible and to give credibility to policies being developed by diverse policy sectors. CONCLUSION: Our findings enrich theoretical understanding in an under-unexplored area of intersectoral action. They also provide policy makers with examples of HiAP across wealthy welfare regimes, and improve understanding of successful HiAP implementation practices, including the win-win approach.

Polymorphisms of the GR and HSD11B1 genes influence body mass index and weight gain during hormone replacement treatment in patients with Addison's disease.

OBJECTIVE: Glucocorticoid substitution is essential in patients with chronic primary adrenocortical insufficiency (Addison's disease) and both over-treatment and inadequate dosage have deleterious effects. Individual sensitivity to glucocorticoids is partly genetically determined. CONTEXT: To test the hypothesis whether the well-characterized SNPs of the GR and HSD11B1 genes may modulate the individual sensitivity to exogenous glucocorticoids and may influence clinical and/or laboratory parameters and the glucocorticoid substitution dosage in patients with Addison's disease. PATIENTS AND METHODS: 68 patients with primary adrenocortical insufficiency were involved. Clinical and laboratory data, as well as the dosage of the hormone replacement therapy were collected. Peripheral blood DNA was isolated, and the GR and HSD11B1 SNPs were examined using allele-specific PCR or Taqman assay on Real Time PCR. RESULTS: The allele frequency of the GR N363S polymorphism was higher in patients compared to the control group and the disease appeared significantly earlier in patients harbouring the GR A3669G compared to noncarriers. These patients had higher ACTH level measured at the time of diagnosis. Homozygous BclI carriers had higher body mass index (BMI) and lower total hydrocortisone equivalent supplementation dose needed than heterozygous or noncarriers. The BMI and weight gain during hormone replacement therapy were also higher in carriers of the HSD11B1 rs4844880 treated with glucocorticoids other than dexamethasone. CONCLUSION: The BclI polymorphism of the GR gene and the rs4844880 of the HSD11B1 gene may contribute to weight gain and may affect the individual need of glucocorticoid substitution dose in these patients.

Combined Methods for Diabetic Retinopathy Screening, Using Retina Photographs and Tear Fluid Proteomics Biomarkers.

Background. It is estimated that 347 million people suffer from diabetes mellitus (DM), and almost 5 million are blind due to diabetic retinopathy (DR). The progression of DR can be slowed down with early diagnosis and treatment. Therefore our aim was to develop a novel automated method for DR screening. Methods. 52 patients with diabetes mellitus were enrolled into the project. Of all patients, 39 had signs of DR. Digital retina images and tear fluid samples were taken from each eye. The results from the tear fluid proteomics analysis and from digital microaneurysm (MA) detection on fundus images were used as the input of a machine learning system. Results. MA detection method alone resulted in 0.84 sensitivity and 0.81 specificity. Using the proteomics data for analysis 0.87 sensitivity and 0.68 specificity values were achieved. The combined data analysis integrated the features of the proteomics data along with the number of detected MAs in the associated image and achieved sensitivity/specificity values of 0.93/0.78. Conclusions. As the two different types of data represent independent and complementary information on the outcome, the combined model resulted in a reliable screening method that is comparable to the requirements of DR screening programs applied in clinical routine.

Economic considerations and health in all policies initiatives: evidence from interviews with key informants in Sweden, Quebec and South Australia.

BACKGROUND: Health in All Policies (HiAP) is a form of intersectoral action that aims to include the promotion of health in government initiatives across sectors. To date, there has been little study of economic considerations within the implementation of HiAP. METHODS: As part of an ongoing program of research on the implementation of HiAP around the world, we examined how economic considerations influence the implementation of HiAP. By economic considerations we mean the cost and financial gain (or loss) of implementing a HiAP process or structure within government, or the cost and financial gain (or loss) of the policies that emerge from such a HiAP process or structure. We examined three jurisdictions: Sweden, Quebec and South Australia. Semi-structured telephone interviews were conducted with 12 to 14 key informants in each jurisdiction. Two investigators separately coded transcripts to identify relevant statements. RESULTS: Initial readings of transcripts led to the development of a coding framework for statements related to economic considerations. First, economic evaluations of HiAP are viewed as important for prompting HiAP and many forms of economic evaluation were considered. However, economic evaluations were often absent, informal, or incomplete. Second, funding for HiAP initiatives is important, but is less important than a high-level commitment to intersectoral collaboration. Furthermore, having multiple sources of funding of HiAP can be beneficial, if it increases participation across government, but can also be disadvantageous, if it exposes underlying tensions. Third, HiAP can also highlight the challenge of achieving both economic and social objectives. CONCLUSIONS: Our results are useful for elaborating propositions for use in realist multiple explanatory case studies. First, we propose that economic considerations are currently used primarily as a method by health sectors to promote and legitimize HiAP to non-health sectors with the goal of securing resources for HiAP. Second, allocating resources and making funding decisions regarding HiAP are inherently political acts that reflect tensions within government sectors. This study contributes important insights into how intersectoral action works, how economic evaluations of HiAP might be structured, and how economic considerations can be used to both promote HiAP and to present barriers to implementation.