Neprilysin activity is increased in metabolic dysfunction-associated steatotic liver disease and normalizes after bariatric surgery or GLP-1 therapy.

Inhibitors of neprilysin improve glycemia in patients with heart failure and type 2 diabetes (T2D). The effect of weight loss by diet, surgery, or pharmacotherapy on neprilysin activity (NEPa) is unknown. We investigated circulating NEPa and neprilysin protein concentrations in obesity, T2D, metabolic dysfunction-associated steatotic liver disease (MASLD), and following bariatric surgery, or GLP-1-receptor-agonist therapy. NEPa, but not neprilysin protein, was enhanced in obesity, T2D, and MASLD. Notably, MASLD associated with NEPa independently of BMI and HbA1c. NEPa decreased after bariatric surgery with a concurrent increase in OGTT-stimulated GLP-1. Diet-induced weight loss did not affect NEPa, but individuals randomized to 52-week weight maintenance with liraglutide (1.2 mg/day) decreased NEPa, consistent with another study following 6-week liraglutide (3 mg/day). A 90-min GLP-1 infusion did not alter NEPa. Thus, MASLD may drive exaggerated NEPa, and lowered NEPa following bariatric surgery or liraglutide therapy may contribute to the reported improved cardiometabolic effects.

Rare Heterozygous Loss-of-Function Variants in the Human GLP-1 Receptor Are Not Associated With Cardiometabolic Phenotypes.

CONTEXT: Lost glucagon-like peptide 1 receptor (GLP-1R) function affects human physiology. OBJECTIVE: This work aimed to identify coding nonsynonymous GLP1R variants in Danish individuals to link their in vitro phenotypes and clinical phenotypic associations. METHODS: We sequenced GLP1R in 8642 Danish individuals with type 2 diabetes or normal glucose tolerance and examined the ability of nonsynonymous variants to bind GLP-1 and to signal in transfected cells via cyclic adenosine monophosphate (cAMP) formation and ß-arrestin recruitment. We performed a cross-sectional study between the burden of loss-of-signaling (LoS) variants and cardiometabolic phenotypes in 2930 patients with type 2 diabetes and 5712 participants in a population-based cohort. Furthermore, we studied the association between cardiometabolic phenotypes and the burden of the LoS variants and 60 partly overlapping predicted loss-of-function (pLoF) GLP1R variants found in 330 566 unrelated White exome-sequenced participants in the UK Biobank cohort. RESULTS: We identified 36 nonsynonymous variants in GLP1R, of which 10 had a statistically significant loss in GLP-1-induced cAMP signaling compared to wild-type. However, no association was observed between the LoS variants and type 2 diabetes, although LoS variant carriers had a minor increased fasting plasma glucose level. Moreover, pLoF variants from the UK Biobank also did not reveal substantial cardiometabolic associations, despite a small effect on glycated hemoglobin A1c. CONCLUSION: Since no homozygous LoS nor pLoF variants were identified and heterozygous carriers had similar cardiometabolic phenotype as noncarriers, we conclude that GLP-1R may be of particular importance in human physiology, due to a potential evolutionary intolerance of harmful homozygous GLP1R variants.

Physician-led medication reviews in polypharmacy patients treated with at least 12 medications in a type 2 diabetes outpatient clinic: A randomised trial.

AIMS: Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician-led medication reviews and increased cross-sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic. METHODS: This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross-sectoral communication. The primary outcome was the number of medications used after six months. Health-related quality of life was quantified using the EuroQoL 5-dimension 5-level (EQ5D-5 L) questionnaire. RESULTS: We recruited 50 participants with a median age of 72 (IQR 67-75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health-related quality of life (EQ5D-5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221). CONCLUSIONS: Physician-led medication reviews and increased cross-sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health-related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable.

Use of GLP-1 receptor agonists and subsequent risk of alcohol-related events. A nationwide register-based cohort and self-controlled case series study.

Animal studies have related glucagon-like peptide 1 receptor agonists (GLP-1) to lower alcohol intake. We examined whether GLP-1 was associated with risk of alcohol-related events in a nationwide cohort study and a self-controlled case series analysis including all new users of GLP1 (n = 38 454) and dipeptidyl peptidase 4 inhibitors (DPP4) (n = 49 222) in Denmark 2009-2017. They were followed for hospital contacts with alcohol use disorder or purchase of drugs for treatment of alcohol dependence in nationwide registers from 2009 to 2018. Associations were examined using Cox proportional hazard and conditional Poisson regression. During follow-up of median 4.1 years, 649 (0.7%) of participants were registered with an alcohol-related event. Initiation of GLP-1 treatment was associated with lower risk of an alcohol-related event (Hazard ratio = 0.46 (95%CI: 0.24-0.86) compared with initiation of DPP4 during the first 3 months of follow-up. Self-controlled analysis showed the highest risk of alcohol-related events in the 3-month pretreatment period (incidence rate ratio [IRR] = 1.25 (1.00-1.58)), whereas the risk was lowest in the first 3-month treatment period (IRR = 0.74 (0.56-0.97). In conclusion, compared with DPP4 users, individuals who start treatment with GLP-1 had lower incidence of alcohol-related events both in cohort and self-controlled analyses. Thus, there might be a transient preventive effect of GLP1 on alcohol-related events the first months after treatment initiation.

[The role of sex hormones in the pathogenesis of melasma].

Facial melasma is a common, acquired, skin condition, which typically presents itself as symmetric hyperpigmentation. It is multifactorial, and hormonal influence is one of the most dominant aetiologies. This review investigates the link between sex hormones and facial melasma. Ten studies were identified, and they overall conclude, that oestrogens play a role in the pathogenesis of melasma in females but not in males. Progesterone, follicle-stimulating hormone and lutropin play no significant role in males or females, while testosterone possibly plays a role in males.

On measurements of glucagon secretion in healthy, obese, and Roux-en-Y gastric bypass operated individuals using sandwich ELISA.

Glucagon is a key regulator of metabolism and is used in the diagnostic of neuroendocrine tumors. Accurate measurement of glucagon requires both extreme sensitivity and specificity since several peptides are derived from the same proglucagon precursor encoding part of the glucagon sequence and given that glucagon circulates in picomolar concentrations. A sandwich ELISA was recently developed and extensively evaluated; however, this method may not be accurate when measuring glucagon in patients with an enhanced production of proglucagon-derived peptides as seen after Roux-en-Y gastric bypass (RYGB). To overcome this, a modified version of the ELISA was developed. In this study, we evaluate an unmodified and a modified version of the ELISA in healthy individuals, individuals with obesity, and finally in two cohorts of patients following RYGB surgery using different nutrient stimuli to assess glucagon dynamics. Finally, in vitro spike-in recoveries using native glucagon and proglucagon-derived peptides were performed in buffer and in plasma. Our data support that both versions of the ELISA accurately capture endogenous and exogenous glucagon in healthy individuals and in individuals with obesity. However, the unmodified version of the assay may overestimate glucagon levels in patients following RYGB in line with minimal but consistent cross-reactivity to oxyntomodulin and glicentin that both are 50-fold increased after RYGB. Importantly, we did not find any changes between the two protocols at fasted conditions and therefore diagnostics of glucagonomas is not affected by the choice of assay procedure nor the surgical history of the patient (RYGB).

A single dose of exenatide had no effect on blood flow velocity in the middle cerebral artery in elderly healthy volunteers: Randomized, placebo-controlled, double-blind clinical trial.

Background and aims: Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) are widely used for the treatment of type 2 diabetes, and recent studies indicate that they may be cardio- and neuroprotective. The safety and effect of a single dose of exenatide, a short-acting GLP-1RA, on cerebral and peripheral arterial function remain unknown. Methods: In this randomized, double-blind pilot trial, we assigned elderly healthy volunteers without diabetes and no previous history of stroke to receive a single dose of subcutaneous exenatide (5 µg) or placebo. Primary outcome was immediate changes over time in blood flow velocity of the middle cerebral arteries (VMCA) assessed by repeated transcranial Doppler measurements. Secondary outcomes were changes in peripheral arterial function with finger plethysmography, ankle-brachial index (ABI), and inflammatory- and endothelial-specific biomarkers. Results: Healthy volunteers (13 women and 17 men) were included: (mean ± standard deviation) age: 62 ± 8 years; body weight: 79.6 ± 12.7 kg; VMCA: 65.3 ± 10.7 cm/s; fasting plasma glucose: 5.5 ± 0.5 mmol/L; HbA1c: 33.9 ± 4.1 mmol/mol (5.3 ± 0.38%). No differences between exenatide and placebo group were seen regarding VMCA (p = 0.058), systolic ABI (p = 0.71), plethysmography (p = 0.45), tumor necrosis factor (p = 0.33), interleukin-6 (p = 0.11), interleukin-1ß (p = 0.34), vascular cell adhesion molecule 1 (p = 0.73), intercellular adhesion molecule 1 (p = 0.74), or E-selectin (p = 0.31). No severe adverse events were observed. Conclusion: A single dose of exenatide did not change cerebral blood flow velocity or peripheral vessel function in elderly healthy volunteers. The medication was safe to use in persons without diabetes allowing us to investigate this drug further in search of the neuroprotective mechanisms. Clinical Trial Registration: https://clinicaltrials.gov, Identifier NCT02838589.

Effects of Ketone Bodies on Brain Metabolism and Function in Neurodegenerative Diseases.

Under normal physiological conditions the brain primarily utilizes glucose for ATP generation. However, in situations where glucose is sparse, e.g., during prolonged fasting, ketone bodies become an important energy source for the brain. The brain's utilization of ketones seems to depend mainly on the concentration in the blood, thus many dietary approaches such as ketogenic diets, ingestion of ketogenic medium-chain fatty acids or exogenous ketones, facilitate significant changes in the brain's metabolism. Therefore, these approaches may ameliorate the energy crisis in neurodegenerative diseases, which are characterized by a deterioration of the brain's glucose metabolism, providing a therapeutic advantage in these diseases. Most clinical studies examining the neuroprotective role of ketone bodies have been conducted in patients with Alzheimer's disease, where brain imaging studies support the notion of enhancing brain energy metabolism with ketones. Likewise, a few studies show modest functional improvements in patients with Parkinson's disease and cognitive benefits in patients with-or at risk of-Alzheimer's disease after ketogenic interventions. Here, we summarize current knowledge on how ketogenic interventions support brain metabolism and discuss the therapeutic role of ketones in neurodegenerative disease, emphasizing clinical data.

Hypercortisolism in Newly Diagnosed Type 2 Diabetes: A Prospective Study of 384 Newly Diagnosed Patients.

Cross-sectional studies in small and selected populations report a high prevalence of hypercortisolism in patients with type 2 diabetes (T2D), which could have therapeutic implications, if confirmed. We therefore estimated the prevalence of hypercortisolism in a large and unselected cohort of recently diagnosed T2D patients. Consecutive patients with recently diagnosed T2D first underwent an overnight dexamethasone (1 mg) suppression test (OD). Patients not suppressing serum cortisol ≤50 nmol/l proceeded with a 48-h low dose dexamethasone suppression test (LDDST) and 24-h urinary free cortisol collection (UFC). Patients with elevated cortisol levels according to LDDST and/or UFC underwent imaging guided by plasma ACTH levels, and assessment of bone mineral density. A total of 384 T2D patients (232male/152 females) with a mean age of 60±10 years were included. Eighty-five (22%) patients suppressed incompletely to OD of whom 20 (5%) failed to suppress after LDDST and/or had elevated UFC (=hypercortisolism). Patients with hypercortisolism did not differ as regards age, BMI, HbA1c, T-score or blood pressure, but a higher proportion of them received antihypertensive treatment (100% vs. 64%, p=0.001). Imaging revealed adrenal adenoma(s) in 9 cases and a pituitary macroadenoma in 1 case. We found a 5% prevalence of hypercortisolism in unselected, recently diagnosed T2D, which was not associated with a persuasive cushingoid phenotype. The clinical implications are therefore uncertain.

Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile.

PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long-term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80°C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications.

Prevalence of micro- and macrovascular diabetes complications at time of type 2 diabetes diagnosis and associated clinical characteristics: A cross-sectional baseline study of 6958 patients in the Danish DD2 cohort.

AIMS: To examine the prevalence of micro- and macrovascular complications and their associated clinical characteristics at time of type 2 diabetes (T2D) diagnosis. METHODS: We examined the prevalence of complications and associated clinical characteristics among 6958 newly diagnosed T2D patients enrolled in the prospective Danish Center for Strategic Research in T2D cohort during 2010-2016. We calculated age- and gender-adjusted prevalence ratios (aPRs) of complications using log-binomial and Poisson regression. RESULTS: In total, 35% (n=2456) T2D patients had diabetic complications around diagnosis; 12% (n=828) had microvascular complications, 17% (n=1186) macrovascular complications, and 6% (n=442) had both. HbA1c levels of ≥7% were associated with microvascular complications [HbA1c 7%-8%; aPR: 1.35, 95% confidence interval (CI): 1.12-1.62] but not macrovascular complications [aPR: 0.91, 95% CI: 0.76-1.08]. High C-peptide≥800pmol/L was associated with macrovascular [aPR 1.34, 95% CI: 1.00-1.80] but not microvascular [aPR 0.97, 95% CI: 0.71-1.33] complications. Macrovascular complications were associated with male sex, age>50years, obesity, hypertriglyceridemia, low HDL cholesterol, smoking, elevated CRP levels, and anti-hypertensive therapy. Microvascular complications were associated with high blood pressure, hypertriglyceridemia, and absence of lipid-lowering therapy. CONCLUSIONS: One-third of patients with T2D had diabetes complications around time of diagnosis. Our findings suggest different pathophysiological mechanisms behind micro- and macrovascular complications.

Cardiovascular effects of current and future anti-obesity drugs.

The prevalence of obesity increases and is associated with increases in co-morbidities e.g. type 2 diabetes, hyperlipidemia, hypertension, obstructive sleep apnea, heart disease, stroke, asthma, several forms of cancer, depression, and may result in reduction of expected remaining lifespan. We have reviewed the adverse effects on the cardiovascular system of anti-obesity drugs now retracted from the market as well as the cardiovascular profile of current drugs and potential pathways which are considered for treatment of obesity. Fenfluramine, and sibutramine were withdrawn due to increased cardiovascular risk, while an inverse agonist at cannabinoid type 1 (CB1) receptors, rimonobant was withdrawn due to serious psychiatric problems. At present there are only few treatments available including orlistat and, phentermine alone or in combination with topiramate and lorcaserin, although cardiovascular side effects need to be clarified regarding phentermine and lorcaserin. Drugs approved for type 2 diabetes including glucagon like peptide (GLP-1) analogues and metformin also cause moderate weight losses and have a favourable cardiovascular profile, while the anti-obesity potential of nebivolol remains unexplored. Pathways with anti-obesity potential include sirtuin activation, blockade of transient receptor potential (TRPV1) channels, acetyl-CoA carboxylase 1 and 2 inhibitors, uncoupling protein activators, bile acids, crotonins, CB1 antagonists, but the cardiovascular profile remains to be investigated. For type 2 diabetes, new drug classes with possible advantageous cardiovascular profiles, e.g. GLP-1 analogues and sodium-glucose co-transport type 2 inhibitors, are associated with weight loss and are currently being evaluated as anti-obesity drugs.

Metallic gold beads in hyaluronic acid: a novel form of gold-based immunosuppression? Investigations of the immunosuppressive effects of metallic gold on cultured J774 macrophages and on neuronal gene expression in experimental autoimmune encephalomyelitis.

Multiple sclerosis (MS) is a neurodegenerative disease caused by recurring attacks of neuroinflammation leading to neuronal death. Immune-suppressing gold salts are used for treating connective tissue diseases; however, side effects occur from systemic spread of gold ions. This is limited by exploiting macrophage-induced liberation of gold ions (dissolucytosis) from gold surfaces. Injecting gold beads in hyaluronic acid (HA) as a vehicle into the cavities of the brain can delay clinical signs of disease progression in the MS model, experimental autoimmune encephalitis (EAE). This study investigates the anti-inflammatory properties of metallic gold/HA on the gene expression of tumor necrosis factor (Tnf-α), Interleukin (Il)-1ß, Il-6, Il-10, Colony-stimulating factor (Csf)-v2, Metallothionein (Mt)-1/2, Bcl-2 associated X protein (Bax) and B cell lymphoma (Bcl)-2 in cultured J774 macrophages and in rodents with early stages of EAE. Cells grew for 5 days on gold/HA or HA, then receiving 1,000 ng/mL lipopolysaccharide (LPS) as inflammatory challenge. In the EAE experiment, 12 Lewis rats received gold injections and control groups included 11 untreated and 12 HA-treated EAE rats and five healthy animals. The experiment terminated day 9 when the first ten animals showed signs of EAE, only one of which were gold-treated (1p = 0.0367). Gene expression in the macrophages showed a statistically significant decrease in Il-6, Il-1ß and Il-10-response to LPS; interestingly HA induced a statistically significant increase of Il-10. In the EAE model gene expression of inflammatory cytokines increased markedly. Compared to EAE controls levels of Tnf-α, Il-1ß, Il-10, Il-6, IL-2, Ifn-γ, Il-17, transforming growth factor (Tgf)-ß, superoxide dismutase (Sod)-2, Mt-2 and fibroblast growth factor (Fgf)-2 were lower in the gold-treated group. HA-treated animals expressed similar or intermediate levels. Omnibus testing for reduced inflammatory response following gold-treatment was not significant, but tendencies towards a decrease in the Sod-2, Fgf-2, Il-1ß response and a higher Bdnf and IL-23 gene expression were seen. In conclusion, our findings support that bio-liberation of gold from metallic gold surfaces have anti-inflammatory properties similar to classic gold compounds, warranting further studies into the pharmacological potential of this novel gold-treatment and the possible synergistic effects of hyaluronic acid.

Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.

INTRODUCTION: Type 2 diabetes (DM-2) increases the risk of developing Alzheimer´s disease (AD), and patients with AD are more likely to develop DM-2. DM-2 and AD share some pathophysiological features. In AD, amyloid-ß (Aß) is accumulated as extracellular plaques in the gray matter of the brain, while in DM-2 islet amyloid polypeptide (IAPP) is accumulated in the pancreas. Premature cellular degeneration is seen in both diseases. Glucagon-like peptide-1 (GLP-1) reduces the amount of Aß and improves cognition in animal studies. The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aß in patients with AD. MATERIAL AND METHODS: This is a randomized, controlled, double-blinded intervention study with AD patients treated for six months with liraglutide (n = 20) or placebo (n = 20). The primary outcome is change in deposition of Aß in the central nervous system (CNS) by Pittsburgh compound B positron emission tomography (PET). The secondary outcome is evaluation of cognition using a neuro-psychological test battery, and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET. Finally, a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow. CONCLUSION: No registered drug affects the deposition of Aß in the brain of AD patients. Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aß plaques and thereby presumably improves the cognitive function. FUNDING: The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Scandinavia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01469351.

Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes.

BACKGROUND: Linagliptin is an oral antihyperglycemic agent that selectively inhibits the enzyme dipeptidyl peptidase-4 (DPP-4). Inhibition of DPP-4 increases the levels of the incretin hormones glucagon-like peptide and glucose-dependent insulinotropic polypeptide by preventing their degradation. OBJECTIVE: We reviewed the role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes. METHODS: A comprehensive literature search was performed using the term "linagliptin." Original research articles and review articles were included in our examination. RESULTS: Linagliptin has a similar mode of action as other gliptins, with comparable efficacy, safety profile, and tolerability. Differences in pharmacokinetic parameters that distinguish linagliptin from other gliptins include that linagliptin is not renally excreted and does not require dose reduction with renal impairment. CONCLUSION: Linagliptin is an oral, once-daily, antihyperglycemic agent that significantly reduces glycated hemoglobin (HbA(1c)) when used alone or in combination with other antidiabetic drugs in people with type 2 diabetes. Pharmacokinetics, such as the lack of renal excretion, distinguishes linagliptin from other gliptins.

ZnT3: a zinc transporter active in several organs.

The review collects the emerging information about zinc transporter 3 (ZnT3). ZnT3 has been associated with Alzheimer's disease, airway diseases and diabetes. ZnT3 was discovered and cloned in 1996. Since then, the major interest in the protein has been in its ability to transport zinc into pre-synaptic vesicles of glutamatergic neurones and its role during the development of amyloid ß plaques in Alzheimer's disease. Increasing evidence suggests that ZnT3 is present in various cell types like different cell types in the brain, cells from adipose tissue, beta-cells from pancreatic islets, epithelial cells, cells from testis, prostate cancer cells and cells from retina. The expression of ZnT3 is regulated by age, hormones, fatty acids, zinc chelation, and glucose.

[Successful treatment of diabetic gustatory hyperhidrosis with topical glycopyrrolate]. / Vellykket behandling af diabetisk gustatorisk hyperhidrose med lokalappliceret glykopyrrolat.

Gustatory hyperhidrosis is a condition characterised by excessive craniofacial sweating in relation to food intake and is associated with diabetic neuropathy. The existing guidelines for treatment of this condition include antiperspirants, oral anticholinergic treatment, ionophoresis, botulinum toxin injections and endothoracic surgery. In this case a patient with diabetes suffering from gustatory hyperhidrosis was treated successfully with topical glycopyrrolate, an anticholinergic agent applied directly on the affected area.

Uptake of silver from metallic silver surfaces induces cell death and a pro-inflammatory response in cultured J774 macrophages.

In clinical medicine metallic silver is used as anti-bacterial coating on various catheters, bandages and prostheses. By means of dissolucytosis, i.e. extracellular macrophage-mediated bio-liberation of metal ions, silver ions are continuously liberated from silver surfaces starting within minutes of exposure. The present study investigates how bio-liberation and subsequent cellular uptake of silver ions affects cell viability and cell signalling within the first 3-24 hours of exposure when J774 macrophages are grown directly on a silver surface. Autometallography (AMG) was applied to demonstrate cytoplasmatic silver uptake and localisation after 1, 3, 12 and 24 hours of exposure to metallic silver. From 12 hours onwards the cells were completely filled with silver enhanced silver-sulphur nanocrystals (AMG-silver grains). At the ultrastructural level, the silver accumulations were located to lysosome-like structures. An immunoassay cell death kit found silver-induced apoptosis after 12 and 24 hours of exposure. Necrosis was seen at the same times. Judged by mRNA analysis silver exposure statistically significantly induces TNF-α and m-CSF gene expression, especially at 3 hours. Furthermore, anti-inflammatory IL-10 transcription is reduced by silver uptake and 24 hours of silver exposure induces massive iNOS-2 gene expression. At the same time silver exposure increases the gene expression of metallothionein (MT-I/MT-II), a cystein-rich protein known for its role in detoxifying heavy metals. Our data suggest that silver ions liberated from metallic silver surfaces accumulate in lysosomes, reduce macrophage viability by apoptosis and necrosis and induce a pro-inflammatory response.

[Vaginal oestrogen therapy in women with hormone-sensitive breast cancer]. / Vaginal østrogenbehandling ved hormonfølsom brystkræft.

Vaginal atrophy is a common problem in women who have previously been treated for breast cancer. Endocrine therapy plays an essential role in the treatment of breast cancer. Systemic hormonal treatment is contraindicated. Topical oestrogens are an effective treatment for vaginal atrophy, but are poorly studied in this group of patients. Physicians are reluctant to recommend it because of the potential increase in the risk of recurrence. The sparse data available suggest that vaginal oestrogen may be used relatively safely by women who are in tamoxifen treatment, but should not be used by women who receive aromatase inhibitor treatment.

Decreased lipid intermediate levels and lipid oxidation rates despite normal lipolysis in patients with hypothyroidism.

BACKGROUND: Hypothyroidism decreases energy expenditure and combustion of fuels, but the reported effects on lipid metabolism and insulin sensitivity are divergent and there is a lack of studies assessing rates of lipolysis and lipid oxidation. The present study was conducted to test the hypotheses that hypothyroidism decreases lipolysis, blood concentrations of free fatty acid, lipid oxidation, and insulin sensitivity. METHODS: We studied 11 hypothyroid patients (thyroid-stimulating hormone: 150 mU/L) with autoimmune thyroiditis (i) before and (ii) after 2 months of triiodothyronine-euthyroidism upon levothyroxine treatment and (iii) compared the patients to 10 healthy volunteers. Subjects underwent a 3-hour study in the basal state followed by a 3-hour euglycemic clamp study, and we used a combination of lipid blood concentrations, palmitate tracer dilution, and indirect calorimetry to assess lipid metabolism. RESULTS: Compared to euthyroid control subjects and/or euthyroid posttreatment values hypothyroid patients were characterized by (i) 40%-50% decreased concentrations of plasma free fatty acids, palmitate, and 3-OH-butyrate (p < 0.05); (ii) >50% decreased lipid oxidation by indirect calorimetry (p < 0.001); (iii) unchanged whole-body lipolysis by palmitate dilution (all p's > 0.45); (iv) 50% increased triglyceride levels (p < 0.05); and (v) approximately 30% decreased insulin sensitivity judged by glucose infusion rate values (p = 0.05). CONCLUSIONS: Our data show that hypothyroidism leads to decreased concentrations and oxidation rates of lipid intermediates and increased triglyceride concentrations in the presence of unaltered rates of lipolysis. The combination of normal lipolysis, low lipid oxidation rates, and high triglyceride concentrations is compatible with increased triglyceride synthesis.