Diabetes: impaired damage control

A coordinated response by the innate immune system, (micro)circulation and nervous system is needed to limit tissue destruction and to initiate reparative processes after tissue damage. Alterations in danger signals in diabetes can be an important cause of the excessive tissue loss and defective tissue repair after injury and can contribute to the higher rates of cardiac failure after myocardial infarction, more severe tissue loss in the case of peripheral ischaemia and impaired wound healing. Here we discuss the mechanisms underlying this impaired damage control in diabetes, with an emphasis on the proinflammatory cytokine high mobility group box 1 and the potential role of dipeptidyl peptidase IV inhibition in improving repair responses

Hereditary paragangliomas : clinical characteristics and genotype-phenotype associations

The findings of the present thesis can be summarized in the following conclusions: 1. In Leiden, the so-called ‘founder effect’ resulted in genetic clustering with an extremely high prevalence of one single SDHD mutation, the SDHD-c.274G>T (p.Asp92Tyr) mutation. 2. Patients with head-and-neck paragangliomas have a considerable impairment of quality of life. 3. Patients with head-and-neck paragangliomas have serious subjective sleep complaints. 4. Patients with SDHD-associated head-and-neck paragangliomas have an increased risk for development of pheochromocytomas and paragangliomas at other locations and life long, repetitive follow up with protocolized clinical, biochemical and radiological screening is therefore mandatory. 5. The use of [123I]-MIBG for detection of intra- and extra-adrenal paragangliomas combined, revealed a sensitivity and specificity of only 80% and 75%, respectively. The sensitivity is dependent on tumor localization and tumor behavior, with an increase in sensitivity to 92% if (intra-adrenal) pheochromocytomas are investigated separately. 6. The practical clinical implications of non-secreting intra-adrenal paragangliomas are currently uncertain. 7. Patients with SDHD mutations have malignant disease in at least ~2.5% of the cases. 8. Mediastinal paragangliomas are associated with mutations in the succinate dehydrogenase genes (either SDHB or SDHD) and aggressive behavior and might be more prevalent than hitherto appreciated. 9. Although the consequences of missing non-secreting and mediastinal paragangliomas in an SDHD-associated population are currently unclear, their possible presence should be taken into consideration in the development of future screening protocols. 10. In the future, [18F]-FDOPA and/or [18F]-FDA are expected to (at least partly) replace MIBG in diagnostic imaging for pheochromocytoma and paraganglioma.LUMC / Geneeskund

Synthetic smooth muscle cell phenotype is associated with increased nicotinamide adenine dinucleotide phosphate oxidase activity: Effect on collagen secretion

ObjectiveSmooth muscle cells (SMCs) from prosthetic vascular grafts secrete higher levels of collagen than aortic SMCs under basal conditions and during incubation with oxidized low-density lipoprotein. We postulated that reactive oxygen species (ROS) contributed to the observed difference. The objective of this study was to assess the effect of ROS on collagen secretion by aortic and graft SMCs and explore the mechanism involved.MethodsSMCs isolated from canine aorta or Dacron thoracoabdominal grafts were incubated with 6-anilinoquinoline-5,8-quinone (LY83583), an agent that induces superoxide production. Type I collagen in the conditioned medium was measured by enzyme-linked immunosorbent assay, and superoxide anion production was measured by lucigenin assay.ResultsLY83583 stimulated a rapid increase in collagen production by graft SMCs that paralleled the LY83583-induced increase in superoxide production. The increase in both collagen and superoxide was greater in graft SMCs than aortic SMCs. Collagen and superoxide production were inhibited by superoxide scavengers. Nicotinamide adenine dinucleotide phosphate (NADPH) induced significantly more superoxide production by graft SMCs than aortic SMCs, suggesting that the NADPH oxidase system was more active in graft SMCs. NADPH oxidase inhibitors blocked the superoxide and collagen production induced by LY83583.ConclusionIn SMCs, the synthetic phenotype is associated with increased NADPH oxidase activity and elevated superoxide production in response to an oxidative stress. Superoxide, in turn, leads to increased collagen production.Clinical RelevanceThe inflammatory process after prosthetic vascular graft implantation causes oxidative stress that can stimulate collagen production by graft SMCs, contributing to the progression of intimal hyperplasia. The exaggerated response of graft SMCs to oxidative stress offers a potential target for therapeutic interventions

Building, Reality, Caring: What Nurses in Three Australian Psychogeriatric Assessment Units Say about the Built Environment

Many people believe that ‘purpose-built’ facilities will diminish some of the challenging behaviours exhibited by older people with dementia or psychiatric conditions. This study aimed to explore and understand what hands-on nurses in psychogeriatric assessment units experience and think of the built environment as a part of their day to day work. Twenty-one unstructured interviews were conducted with nurses at three psychogeriatric assessment units. The units ranged in style from an ancient adapted building to a contemporary 'purpose-built' facility. A critical hermeneutics derived from Gadamer was used to explore the interviews. It found that nurses think of the built environment in relation to the care needs of their patients, and feel bureaucratic restrictions in using the built environment more keenly than the shortcomings of the built environment itself. Nurses saw themselves and their patients as 'outcasts' or victims of those with money and power. The study concludes with suggestions for challenging the status quo, but also considers that being regarded as 'outcasts' allows opportunities to avoid being overly impressed by technological marvels

Anacetrapib reduces progression of atherosclerosis, mainly by reducing non-HDL-cholesterol, improves lesion stability and adds to the beneficial effects of atorvastatin

The present study is the first intervention study in a well-established, translational mouse model for hyperlipidaemia and atherosclerosis showing that anacetrapib dose-dependently reduces atherosclerosis development and adds to the anti-atherogenic effects of atorvastatin. This effect is mainly ascribed to the reduction in non-HDL-C despite a remarkable increase in HDL-C and without affecting HDL functionality. In addition, anacetrapib improves lesion stabilit

Evidence for a direct effect of the NAD+ precursor acipimox on muscle mitochondrial function in humans.

Recent preclinical studies showed the potential of nicotinamide adenine dinucleotide (NAD(+)) precursors to increase oxidative phosphorylation and improve metabolic health, but human data are lacking. We hypothesize that the nicotinic acid derivative acipimox, an NAD(+) precursor, would directly affect mitochondrial function independent of reductions in nonesterified fatty acid (NEFA) concentrations. In a multicenter randomized crossover trial, 21 patients with type 2 diabetes (age 57.7 +/- 1.1 years, BMI 33.4 +/- 0.8 kg/m(2)) received either placebo or acipimox 250 mg three times daily dosage for 2 weeks. Acipimox treatment increased plasma NEFA levels (759 +/- 44 vs. 1,135 +/- 97 mumol/L for placebo vs. acipimox, P < 0.01) owing to a previously described rebound effect. As a result, skeletal muscle lipid content increased and insulin sensitivity decreased. Despite the elevated plasma NEFA levels, ex vivo mitochondrial respiration in skeletal muscle increased. Subsequently, we showed that acipimox treatment resulted in a robust elevation in expression of nuclear-encoded mitochondrial gene sets and a mitonuclear protein imbalance, which may indicate activation of the mitochondrial unfolded protein response. Further studies in C2C12 myotubes confirmed a direct effect of acipimox on NAD(+) levels, mitonuclear protein imbalance, and mitochondrial oxidative capacity. To the best of our knowledge, this study is the first to demonstrate that NAD(+) boosters can also directly affect skeletal muscle mitochondrial function in humans

Pediatric Differentiated Thyroid Carcinoma in The Netherlands: A Nationwide Follow-Up Study

Introduction: Treatment for differentiated thyroid carcinoma (DTC) in pediatric patients is based mainly on evidence from adult series due to lack of data from pediatric cohorts. Our objective was to evaluate presentation, treatment-related complications, and long-term outcome in patients with pediatric DTC in the Netherlands. Patients and methods: In this nationwide study, presentation, complications and outcome of patients with pediatric DTC (age at diagnosis ≤18 years) treated in the Netherlands between 1970 and 2013 were assessed using medical records. Results: We identified 170 patients. Overall survival was 99.4% after median follow-up of 13.5 (range 0.3–44.7) years. Extensive follow-up data were available for 105 patients (83.8% women), treated in 39 hospitals. Median age at diagnosis was 15.6 (range 5.8–18.9) years. At initial diagnosis, 43.8% of the patients had cervical lymph node metastases; 13.3% had distant metastases. All patients underwent total thyroidectomy. Radioiodine was administered to 97.1%, with a median cumulative activity of 5.66 (range 0.74–35.15) GBq. Lifelong postoperative complications (permanent hypoparathyroidism and/or recurrent laryngeal nerve injury) were present in 32.4% of the patients. At last known follow-up, 8.6% of the patients had persistent disease and 7.6% experienced a recurrence. TSH suppression was not associated with recurrences (OR 2.00, 95% CI 0.78 to 5.17, P = 0.152). Conclusions: Survival of pediatric DTC is excellent. Therefore, minimizing treatment-related morbidity takes major priority. Our study shows a frequent occurrence of lifelong postoperative complications. Adverse effects may be reduced by centralization of care, which is crucial for children with DTC

MEN1 redefined, a clinical comparison of mutation-positive and mutation-negative patients

Contains fulltext : 170909.pdf (publisher's version ) (Open Access)BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up. METHODS: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. RESULTS: A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001). CONCLUSIONS: Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors