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Objective: It is urgent to diagnose giant cell arteritis (GCA) as quickly as possible to prevent irreversible blindness. The traditional gold standard for diagnosing GCA is temporal artery biopsy (TAB). However, TAB lacks diagnostic performance and carries out risks of surgical intervention. The noninvasive color Doppler ultrasound (CDU) seems to be a promising alternative. This study is designed to assess the diagnostic value of CDU in daily clinical practice., Methods: In this prospective cohort study, patients with a clinical suspicion of active GCA were included and underwent a CDU of the temporal arteries. If deemed necessary by the referrer, a TAB and/or 18F-fluorodeoxyglucose positron emission tomography with computed tomography was performed. The retrospective clinical diagnosis was determined 1 year after inclusion by two physicians experienced in the field of vasculitis., Results: 242 patients were included and GCA was diagnosed in 73 (30%) patients by the defined retrospective clinical diagnosis. Compared with the retrospective diagnosis, CDU has a sensitivity of 60% (48-72), specificity of 94% (89-97), positive predictive value (PPV) of 81% (70-89), negative predictive value (NPV) of 85% (80-88), and an accuracy of 84% (78-88). A total of 84 (35%) patients underwent TAB. TAB has a sensitivity of 66% (51-79), specificity of 100% (90-100), PPV of 100% (100), NPV of 67% (58-75), and an accuracy of 80% (70-88)., Conclusion: This study shows comparable diagnostic performance for CDU and TAB and even better CDU results with a bilateral halo present. Considering the advantages of the noninvasive CDU, it is the diagnostic tool of choice., (© 2023 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Type 1 diabetes (T1D) is characterised by islet autoimmunity and beta cell destruction. A gut microbiota-immunological interplay is involved in the pathophysiology of T1D. We studied microbiota-mediated effects on disease progression in patients with type 1 diabetes using faecal microbiota transplantation (FMT)., Design: Patients with recent-onset (<6 weeks) T1D (18-30 years of age) were randomised into two groups to receive three autologous or allogenic (healthy donor) FMTs over a period of 4 months. Our primary endpoint was preservation of stimulated C peptide release assessed by mixed-meal tests during 12 months. Secondary outcome parameters were changes in glycaemic control, fasting plasma metabolites, T cell autoimmunity, small intestinal gene expression profile and intestinal microbiota composition., Results: Stimulated C peptide levels were significantly preserved in the autologous FMT group (n=10 subjects) compared with healthy donor FMT group (n=10 subjects) at 12 months. Small intestinal Prevotella was inversely related to residual beta cell function (r=-0.55, p=0.02), whereas plasma metabolites 1-arachidonoyl-GPC and 1-myristoyl-2-arachidonoyl-GPC levels linearly correlated with residual beta cell preservation (rho=0.56, p=0.01 and rho=0.46, p=0.042, respectively). Finally, baseline CD4 +CXCR3+T cell counts, levels of small intestinal Desulfovibrio piger and CCL22 and CCL5 gene expression in duodenal biopsies predicted preserved beta cell function following FMT irrespective of donor characteristics., Conclusion: FMT halts decline in endogenous insulin production in recently diagnosed patients with T1D in 12 months after disease onset. Several microbiota-derived plasma metabolites and bacterial strains were linked to preserved residual beta cell function. This study provides insight into the role of the intestinal gut microbiome in T1D., Trial Registration Number: NTR3697., Competing Interests: Competing interests: MN and WMDV are founders and in the Scientific Advisory Board of Caelus Health, the Netherlands. WMDV is Founder and in the Scientific Advisory Board of A-Mansia, Belgium. MN is in the Scientific Advisory Board of Kaleido Biosciences, USA., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

An 82-year-old woman attended our outpatient clinic because of a swollen right arm and hoarseness. Upon raising both arms, the patient developed a red and swollen face (Pemberton's sign). An MRI of the thorax showed a large intrathoracic goitre, which compressed venous structures and limited blood flow even when she lowered her arms.

Importance: Inappropriate use of laboratory testing is a challenging problem. Estimated overuse rates of approximately 20% have been reported. Effective, sustainable solutions to stimulate optimal use are needed., Objective: To determine the association of a multifaceted intervention with laboratory test volume., Design, Setting, and Participants: A before-after quality improvement study was performed between August 1, 2016, and April 30, 2018, in the internal medicine departments of 4 teaching hospitals in the Netherlands. Data on laboratory order volumes from 19 comparable hospitals were used as controls. The participants were clinicians ordering laboratory tests., Interventions: The intervention included creating awareness through education and feedback, intensified supervision of residents, and changes in order entry systems. Interventions were performed by local project teams and guided by a central project team during a 6-month period. Sustainability was investigated during an 8-month follow-up period., Main Outcomes and Measures: The primary outcome was the change in slope for laboratory test volume. Secondary outcomes were change in slope for laboratory expenditure, order volumes and expenditure for other diagnostic procedures, and clinical outcomes. Data were collected on duration of hospital stay, rate of repeated outpatient visits, 30-day readmission rate, and rate of unexpected prolonged duration of hospital stay for patients admitted for pneumonia., Results: The numbers of internists and residents ordering tests in hospitals 1 to 4 were 16 and 30, 18 and 20, 13 and 17, and 21 and 60, respectively. Statistically significant changes in slope for laboratory test volume per patient contact were found at hospital 1 (change in slope, -1.55; 95% CI, -1.98 to -1.11; P < .001), hospital 3 (change in slope, -0.74; 95% CI, -1.42 to -0.07; P = .03), and hospital 4 (change in slope, -2.18; 95% CI, -3.27 to -1.08; P < .001). At hospital 2, the change in slope was not statistically significant (-0.34; 95% CI, -2.27 to 1.58; P = .73). Laboratory test volume per patient contact decreased by 11.4%, whereas the volume increased by 2.4% in 19 comparable hospitals. Statistically significant changes in slopes for laboratory costs and volumes and costs for other diagnostic procedures were also observed. Clinical outcomes were not associated with negative changes. Important facilitators were education, continuous attention for overuse, feedback, and residents' involvement. Important barriers were difficulties in data retrieval, difficulty in incorporation of principles in daily practice, and high resident turnover., Conclusions and Relevance: A set of interventions aimed at changing caregivers' mindset was associated with a reduction in the laboratory test volume in all departments, whereas the volume increased in comparable hospitals in the Netherlands. This study provides a framework for nationwide implementation of interventions to reduce unnecessary laboratory testing.

The purpose of this study was to investigate the psychometric characteristics (content validity, internal consistency, and subscale structure) of the Hematology Information Needs Questionnaire-62 (HINQ-62), a patient reported outcome measure (PROM) for assessing the need for information among patients with hematological malignancies (HM-patients). Baseline data were used from a prospective study on the need for information which 336 newly diagnosed HM-patients had completed. In phase 1 (design phase), data from the first 135 patients were used and in phase 2 (validation phase), data from the remaining 201 HM patients were used. Content validity was analyzed by examining irrelevance of items. Items were considered irrelevant if more than 10% of the patients scored totally disagree on that item. The subscale structure of the HINQ-62 was investigated with Factor analysis (FA) (exploratory FA in phase 1 and confirmatory FA in phase 2). Cronbach's α was computed for the different subscales and >.70 was considered as good internal consistency. None of the 62 HINQ-items were irrelevant. Exploratory FA identified five subscales: "Disease, symptoms, treatment and side-effects", "Etiology, sleep and physical changes", "Self-care", "Medical tests and prognosis", and "Psychosocial". Root Mean Square Error of Approximation (RMSEA) among patients was 0.037 in phase 1 and 0.045 in phase 2. The comparative fit index (CFI)/Tucker-Lewis index -non-normed fit index among patients was 0.984/0.983 and 0.948/0.946, in phase 1 and 2 respectively. The internal consistency of the subscales was good, with Cronbach's α 0.82-0.99. The HINQ is a valid PROM for assessing the need for information among Dutch HM-patients at diagnosis., Competing Interests: The authors have declared that no competing interests exist.

There is a growing interest in using hydrogels for biomedical applications, because of more favourable characteristics. Some of these hydrogels can be activated by using particular stimuli, for example electrical fields. These stimuli can change the hydrogel shape in a predefined way. It could make them capable of adaptation to patient-specific anatomy even post-implantation. This is the first paper aiming to describe in vivo studies of an electro-responsive, Pluronic F127 based hydrogel, for intravascular applications. Pluronic methacrylic acid hydrogel (PF127/MANa) was in vitro tested for its haemolytic and cytotoxic effects. Minimal invasive implantation in the carotid artery of sheep was used to evaluate its medium-term biological effects, through biochemical, macroscopic, radiographic, and microscopic evaluation. Indirect and direct testing of the material gave no indication of the haemolytic effects of the material. Determination of fibroblast viability after 24 h of incubation in an extract of the hydrogel showed no cytotoxic effects. Occlusion was obtained within 1 h following in vivo implantation. Evaluation at time of autopsy showed a persistent occlusion with no systemic effects, no signs of embolization and mild effects on the arterial wall. An important proof-of-concept was obtained showing biocompatibility and effectiveness of a pluronic based electro-responsive hydrogel for obtaining an arterial occlusion with limited biological impact. So the selected pluronic-methacrylic acid based hydrogel can be used as an endovascular occlusion device. More importantly it is the first step in further development of electro-active hydrogels for a broad range of intra-vascular applications (e.g. system to prevent endoleakage in aortic aneurysm treatment, intra-vascular drug delivery).

Objective: Low vitamin D status has been associated with impaired glycemic control in patients with type 2 diabetes. The purpose of our study was to evaluate the effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes., Research Design and Methods: This randomized, double-blind, placebo-controlled trial was conducted in 275 adult patients with type 2 diabetes without insulin treatment. Patients were randomly assigned to receive either vitamin D3 (50,000 IU/month) or placebo for 6 months. To assess the primary outcome of the study, change in HbA(1c), we performed a linear regression analysis., Results: Mean baseline serum 25-hydroxyvitamin D [25(OH)D] increased from 60.6 ± 23.3 to 101.4 ± 27.6 nmol/L and 59.1 ± 23.2 to 59.8 ± 23.2 nmol/L in the vitamin D and placebo group, respectively. Mean baseline HbA(1c) was 6.8 ± 0.5% (51 ± 6 mmol/mol) in both groups. After 6 months, no effect was seen on HbA(1c) (mean difference: β = 0.4 [95% CI -0.6 to 1.5]; P = 0.42) and other indicators of glycemic control (HOMA of insulin resistance, fasting insulin, and glucose) in the entire study population. Subgroup analysis in patients with a serum 25(OH)D <50 nmol/L or an HbA(1c) level >7% (53 mmol/mol) did not differ the results., Conclusions: In a well-controlled group of patients with type 2 diabetes, intermittent high-dose vitamin D supplementation did not improve glycemic control., (© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

For patients with haematological malignancies, information on disease, prognosis, treatment and impact on quality of life is of the utmost importance. To gain insight into the perceived need for information in relation to sociodemographic and clinical parameters, comorbidity, quality of life (QoL) and information satisfaction, we compiled a questionnaire based on existing validated questionnaires. A total of 458 patients diagnosed with a haematological malignancy participated. The perceived need for information was moderate to high (40-70%). Multivariate regression analyses showed that a higher need for information was related to younger age, worse QoL, being member of a patient society and moderate comorbidity. The need for disease and treatment-related information was higher than the need for psychosocial information. A higher need for disease and treatment-related information was associated to being diagnosed with multiple myeloma. A higher need for psychosocial information was related to a lower educational level. The information provision could be improved according to 41% of the patients. Higher satisfaction with provided information was associated with better QoL. Most patients (62%) reported that they wanted to be fully informed about their illness and actively involved in treatment decision-making. The results contribute to improving patient-tailored information provision and shared decision-making in clinical practice., (Copyright © 2014 John Wiley & Sons, Ltd.)

Objective: A haematological malignancy is a serious, life-altering disease and may be characterised as an uncontrollable and unpredictable stress situation. In dealing with potentially threatening information, individuals generally utilise two main cognitive coping styles: monitoring (the tendency to seek threat-relevant information) and blunting (avoiding threatening information and seeking distraction). The aim of this study was to obtain insight into the association between cognitive coping style and (a) need for information, (b) satisfaction with information, (c) involvement in decision making, and (d) quality of life (QoL)., Methods: In this cross-sectional study, coping style was assessed among adult patients diagnosed with a haematological malignancy, using an adapted version of the Threatening Medical Situations Inventory. Information need, information satisfaction, decision-making preference and QoL were measured with validated questionnaires., Results: In total, 458 patients returned the questionnaire (66%). A monitoring coping style was positively related to need for both general and specific information. Blunting was positively and QoL was negatively related to need for information. Monitoring was positively related to involvement in decision-making and negatively to information satisfaction. Using multivariate analysis, this relation between monitoring and information satisfaction disappeared, and for blunting, we found a negatively significant relation. QoL was not related to coping style., Conclusions: Among patients with haematological malignancies, coping style is related to a need for information, information satisfaction, and involvement in treatment decision-making. Therefore, it is important for health care professionals to be aware of individual differences in cognitive coping style., (Copyright © 2014 John Wiley & Sons, Ltd.)

Smart hydrogels for biomedical applications are highly researched materials. However, integrating them into a device for implantation is difficult. This paper investigates an integrated delivery device designed to deliver an electro-responsive hydrogel to a target location inside a blood vessel with the purpose of creating an occlusion. The paper describes the synthesis and characterization of a Pluronic/methacrylic acid sodium salt electro-responsive hydrogel. Application of an electrical bias decelerates the expansion of the hydrogel. An integrated delivery system was manufactured to deliver the hydrogel to the target location in the body. Ex vivo and in vivo experiments in the carotid artery of sheep were used to validate the concept. The hydrogel was able to completely occlude the blood vessel reducing the blood flow from 245 to 0 ml/min after implantation. Ex vivo experiments showed that the hydrogel was able to withstand physiological blood pressures of > 270 mm·Hg without dislodgement. The results showed that the electro-responsive hydrogel used in this paper can be used to create a long-term occlusion in a blood vessel without any apparent side effects. The delivery system developed is a promising device for the delivery of electro-responsive hydrogels.

Background: Besides the classical role of vitamin D on calcium and bone homeostasis, vitamin D deficiency has recently been identified as a contributing factor in the onset of insulin resistance in type 2 diabetes mellitus. However, it is uncertain whether vitamin D deficiency and poor glycaemic control are causally interrelated or that they constitute two independent features of type 2 diabetes mellitus. There are limited clinical trials carried out which measured the effect of vitamin D supplementation on glycaemic control.The objective of this study is to investigate the effect of vitamin D supplementation on glycaemic control and quality of life in patients with type 2 diabetes mellitus., Methods/design: In a randomised double-blind placebo-controlled trial conducted in five general practices in the Netherlands three hundred patients with type 2 diabetes mellitus treated with lifestyle advises or metformin or sulphonylurea-derivatives are randomised to receive either placebo or 50,000 IU Vitamin D3 at monthly intervals. The primary outcome measure is the change in glycated haemoglobin level between baseline and six months. Secondary outcome measures include blood pressure, anthropometric parameters, lipid profile, insulin resistance, quality of life, advanced glycation end products and safety profiles. Quality of life will be measured by The Short Form (SF-36) Health Survey questionnaire. Advanced glycation end products are measured by an AGE-reader., Discussion: This trial will be the first study exploring the effect of vitamin D supplementation on both glycaemic control and quality of life in patients with type 2 diabetes mellitus. Our findings will contribute to the knowledge of the relationship between vitamin D status and insulin resistance in patients with type 2 diabetes mellitus., Trial Registration: The Netherlands trial register: NTR3154.

Importance: Elevated plasma glucose levels in patients with acute coronary syndrome (ACS) on hospital admission are associated with increased mortality. Clinical trials of glucose regulation have provided inconsistent results with respect to cardiovascular outcomes, perhaps because target glucose levels have been suboptimal., Objective: To study the effectiveness and safety of intensive glucose management in patients with ACS who have hyperglycemia, aiming at strict blood glucose normalization., Design, Setting, and Participants: Single-center, prospective, open-label, randomized clinical trial in a large teaching hospital. Patients with ACS with an admission plasma glucose level of 140 to 288 mg/dL were eligible for inclusion and enrolled from July 23, 2008, to February 8, 2012. Patients with insulin-dependent diabetes mellitus were excluded. Informed consent was obtained from 294 patients, who were randomized. Of these, 93.6% received percutaneous coronary intervention (PCI)., Interventions: Intensive glucose management strategy, aiming at a plasma glucose level of 85 to 110 mg/dL by using intravenous insulin, or to conventional expectative glucose management., Main Outcomes and Measures: End points were assessed according to the intention-to-treat principle. The primary end point was high-sensitivity troponin T value 72 hours after admission (hsTropT72); secondary end points, area under the curve of creatine kinase, myocardial band (AUC-CK-MB), release and myocardial perfusion scintigraphy findings at 6 weeks' follow-up., Results: In the intensive management arm, median hsTropT72 was 1197 ng/L (25th and 75th percentiles of distribution, 541-2296 ng/L) vs 1354 ng/L (530-3057 ng/L) in the conventional arm (P = .41). Median AUC-CK-MB was 2372 U/L (1242-5004 U/L) vs 3171 U/L (1620-5337 U/L) (P = .18). The difference in median extent of myocardial injury measured by myocardial perfusion scintigraphy was not significant (2% vs 4%) (P = .07). Severe hypoglycemia (<50 mg/dL) was rare and occurred in 13 patients. Before discharge, death or a spontaneous second myocardial infarction occurred in 8 patients (5.7%) vs 1 (0.7%) (P = .04). CONCLUSIONS AND RELEVANCE Intensive glucose regulation did not reduce infarct size in hyperglycemic patients with ACS treated with PCI, and was associated with harm. Future studies should focus on patients with ACS who have persistently elevated blood glucose after PCI, and should evaluate alternative strategies for optimizing glycemia., Trial Registration: www.trialregister.nl Identifier: NTR1205.

In a 79-year-old female, a markedly elevated alkaline phosphatase level was found by chance. She had noticed her hats had become too small. Clinical examination revealed a large skull with frontal bossing. Bone scintigraphy showed increased activity of bone metabolism in the skull. These three findings combined are considered a classic example of Paget's disease.

A 56-years-old woman was admitted to the emergency department because of fatigue since 6 weeks. Laboratory investigation revealed pancytopenia with teardrop cells and hypersegmentation. Teardrop cells are a characteristic finding in myelofibrosis, but in this case they were caused by severe vitamin B12 deficiency.

Patients with an elevated erythrocyte sedimentation rate (ESR) and non-specific symptoms often pose a diagnostic dilemma. PET/CT visualises infection, inflammation and malignancy, all of which may cause elevated ESR. The objective of this study was to determine the contribution of 18F-fluorodeoxglucose positron emission tomography (PET/CT) in the diagnostic work-up of referred patients with an elevated ESR, in whom initial routine evaluation did not reveal a diagnosis. We conducted a combined retrospective (A) and prospective (B) study in elderly (>50 years) patients with a significantly elevated ESR of ≥ 50 mm/h and non-specific complaints. In study A, 30 patients were included. Malignancy (8 patients), auto-inflammatory disease (8 patients, including 5 with large-vessel vasculitis) and infection (3 patients) were suggested by PET/CT. Two scans showed non-specific abnormalities and 9 scans were normal. Of the 21 abnormal PET/CT results, 12 diagnoses were independently confirmed and two alternative diagnosis were made. Two diagnoses were established in patients with a normal scan. In study B, 58 patients in whom a prior protocolised work-up was non-diagnostic, were included. Of these, 25 PET/CT-scans showed suspected auto-inflammatory disease, particularly large-vessel vasculitis (14 cases). Infection and malignancy was suspected in 5 and 3 cases, respectively. Seven scans demonstrated non-specific abnormalities, 20 were normal. Of the 40 abnormal PET/CT results, 22 diagnoses were confirmed, 3 alternative diagnoses were established. Only one diagnosis was established in the 20 patients with a normal scan. In both studies, the final diagnosis was based on histology, clinical follow-up, response to therapy or additional imaging. In conclusion, PET/CT may be of potential value in the diagnostic work-up of patients with elevated ESR if routine evaluation reveals no diagnosis. In particular, large-vessel vasculitis appears to be a common finding. A normal PET/CT scan in these patients suggests that it is safe to follow a wait-and-see policy.

In patients with hyperglycaemia plus obesity and cardiovascular disease, the diagnosis of type 2 diabetes mellitus is likely to be made and this is usually followed by the start of antihyperglycaemic therapy. This pragmatic approach, however, does not always turn out to be the correct one. We describe two patients with occult conditions that had caused or aggravated diabetes mellitus (DM): a 46-year-old man with acromegaly and a 41-year-old woman with Cushing's disease. After neurosurgeries were performed, the requirement for antihyperglycaemic treatment markedly decreased (case 2) or even disappeared (case 1). Physicians treating patients with DM should ask themselves what the cause of the disease could be; the recognition and treatment of that underlying condition may substantially decrease the amount of insulin required and may even cause the disappearance of DM altogether.

Background: Elevated plasma glucose levels on admission (APG) are very common in patients with acute coronary syndrome (ACS) and can be the first indication of diabetes mellitus., Objective: To provide insight into the prevalence of previously undiagnosed diabetes and to compare different methods of diagnosing diabetes in patients with ACS., Methods: Patients with ACS with elevated APG who participated in the BIOMArCS 2 glucose trial underwent an oral glucose tolerance test (OGTT) prior to discharge. 130 patients were included who underwent metabolic assessment. Of these, 109 had an OGTT and 13 patients had pre-existing diabetes., Results: The OGTT results were categorised as (previously) undiagnosed diabetes in 35% of patients (fasting plasma glucose (FPG) ≥7.0 mmol/l or 2-h post-load glucose ≥11.1 mmol/l) and impaired glucose metabolism in 44% (FPG 6.1-6.9 mmol/l or post-load glucose 7.8-11.0 mmol/l), so only 21% had a normal glucose metabolism. Undiagnosed diabetes could not be adequately predicted with APG, FPG or HbA1c (area under the ROC curve 0.61, 0.75 and 0.72, respectively). Patients with abnormal glucose metabolism were significantly older, had higher admission HbA1c values, a higher Killip classification and more often had a prior stroke than patients with normal glucose metabolism., Conclusion: 79% of hyperglycaemic patients with ACS were found to have abnormal glucose metabolism. As APG, HbA1c and FPG had a low sensitivity to detect undiagnosed diabetes, an OGTT appears to be the best test to assess the presence of previously undiagnosed diabetes or impaired glucose metabolism in hyperglycaemic patients with ACS.

Objective: To quantify the environmental component of aetiology of overweight and obesity by examining the relationship between the degree of overweight in dogs and cats and the degree of overweight in their owners., Design: Cross-sectional study. Main outcome measures of the owners were weight, height (stature) and BMI. Of the animals, weight and divergence from ideal weight were measured by a veterinarian., Setting: Three veterinary clinics in Amsterdam, The Netherlands., Subjects: Dogs and cats, together with their owners, who visited the veterinary clinic. Dogs and cats had to be older than 1 year, and their owners had to be at least 21 years old. After exclusion, there remained forty-seven pairs of dogs and their owners and thirty-six pairs of cats and their owners., Results: We found a significant relationship between the degree of overweight of dogs and the BMI of their owners (r = 0.31). Correction for length of ownership, gender and age of the animal, and gender, age, education level and activity score of the owner did not materially affect this relationship. However, after correction for the amount of time the dog was being walked each day, this relationship disappeared. No significant relationship was found between the degree of overweight of cats and the BMI of their owners., Conclusions: The degree to which dogs are overweight is, in contrast to the degree to which cats are overweight, related to the BMI of their owners.

Hyperglycemia upon admission of myocardial infarction patients predicts inferior clinical outcomes. Current strategies investigating hyperglycemia correction mostly use glucose-driven protocols. Implementation of these often labor-intensive protocols might be facilitated with the approach of a clinical pathway. Therefore, we evaluated the implementation of our glucose-driven protocol.We adapted a protocol for use in our coronary care unit (CCU), which was implemented according to the steps of a clinical pathway. To compensate for carbohydrates in meals we additionally developed a regimen of subcutaneous insulin.Protocol adherence was facilitated with a Web-based insulin calculator. All hyperglycemic patients admitted to the CCU were eligible for treatment according to this protocol.In a 4-month period, 643 glucose measurements were obtained in hyperglycemic patients admitted to our CCU. Patients were treated intensively with IV insulin for 35 hours and had 23 glucose measurements in this time span on average. This regimen achieved a median glucose of 6.2 mmol/L. Severe hypoglycemia occurred in only 1.1% of measurements and was without severe clinical side effects.Introduction of new intensive insulin protocol according to the steps of a clinical pathway is safe and feasible. The presence of a clinical pathway coordinator and sound communication are important conditions for successful introduction, which can be further aided with a computerized calculator.

Hyperglycemia is common among patients admitted with acute coronary syndromes (ACS) and is associated with less favorable clinical outcomes. Guidelines for the treatment of hyperglycemia in myocardial infarction are confusing, partly because of lack of sufficient evidence. Neither do we know what the everyday practice on hyperglycemia in ACS is. Therefore the aim of our study is to describe current glucose management in ACS patients in The Netherlands. We designed a multiple-choice questionnaire that was emailed to all 94 independent cardiology departments of each of the 114 hospitals within The Netherlands. We interviewed cardiologists about their specific hospital setting, the presence, content, and actual use of a dedicated hyperglycemia protocol in the setting of ACS. Ninety-four questionnaires were returned (response rate 100%). Only 32% of the respondents reported to have a routinely applied, dedicated hyperglycemia protocol in the setting of ACS. An admission glucose of 13.0 mmol/L is considered a stress value by 60% of respondents. Treatment of hyperglycemia is postponed until after the acute phase (ie, after >6 hours) in 41% of the cardiology departments and in 76% HbA1c is not routinely measured before discharge. Only a minority of Dutch cardiology departments have a routinely applied, dedicated hyperglycemia protocol for patients admitted with ACS. Different views exist on the interpretation of admission hyperglycemia in patients without previously diagnosed diabetes. Dedicated protocols with well-established treatment goals allow early treatment and are mandatory to improve timely metabolic regulation.

Aim: To investigate the effect of vitamin supplements on homocysteine levels in patients with celiac disease., Methods: Vitamin B6, folate, vitamin B12, and fasting plasma homocysteine levels were measured in 51 consecutive adults with celiac disease [median (range) age 56 (18-63) years; 40% men, 26 (51%) had villous atrophy, and 25 (49%) used B-vitamin supplements] and 50 healthy control individuals matched for age and sex. Finally, the C677T polymorphism of 5,10-methylenetetrahydrofolate reductase (MTHFR) was evaluated in 46 patients with celiac disease and all control individuals., Results: Patients with celiac disease and using vitamin supplements had higher serum vitamin B6 (P = 0.003), folate (P < 0.001), and vitamin B12 (P = 0.012) levels than patients who did not or healthy controls (P = 0.035, P < 0.001, P = 0.007, for vitamin B6, folate, and vitamin B12, respectively). Lower plasma homocysteine levels were found in patients using vitamin supplements than in patients who did not (P = 0.001) or healthy controls (P = 0.003). However, vitamin B6 and folate, not vitamin B12, were significantly and independently associated with homocysteine levels. Twenty-four (48%) of 50 controls and 23 (50%) of 46 patients with celiac disease carried the MTHFR thermolabile variant T-allele (P = 0.89)., Conclusion: Homocysteine levels are dependent on Marsh classification and the regular use of B-vitamin supplements is effective in reduction of homocysteine levels in patients with celiac disease and should be considered in disease management.

A 65-year-old woman was admitted to our hospital with progressive confusion and hypersomnia. During admission she became comatose which was found to be caused by hepatic encephalopathy. Fifteen years earlier she had undergone a Whipple's pancreaticoduodenectomy for an adenocarcinoma of the pancreatic head. She had developed secondary endo- and exocrine pancreas insufficiency and a fatty liver. Non-alcoholic fatty liver disease (NAFLD) is a little-known late complication of a pancreaticoduodenectomy, possibly caused by postoperative exocrine pancreas insufficiency. NAFLD may lead to non-alcoholic steatohepatitis (NASH) which can ultimately result in liver cirrhosis. There have been no previous reports in the literature of hepatic encephalopathy presenting as liver failure secondary to NASH following pancreaticoduodenectomy.

This paper describes the electrochemical characterisation of a range of gold and platinum microelectrode arrays (MEAs) fabricated by standard photolithographic methods. The inter-electrode spacing, geometry, numbers and dimensions of the electrodes in the arrays were found to influence the voltammetric behaviours obtained. Excellent correlation was found between experimental data and theoretical predictions employing published models of microelectrode behaviour. Gold MEAs were evaluated for their applicability to copper determination in a soil extract sample, where agreement was found between the standard analytical method and a method based on underpotential deposition-anodic stripping voltammetry (UPD-ASV) at the MEAs, offering a mercury-free alternative for copper sensing.

Background: Patients with end-stage renal disease as well as mild renal impairment have an increased risk for the development of cardiovascular disease. It has been suggested that advanced glycation end-products (AGEs) are involved in atherogenesis, possibly through induction of endothelial dysfunction and low-grade inflammation., Methods: In a cross-sectional, single-centre study, we investigated four groups of 20 non-diabetic subjects with a creatinine clearance ranging from normal (> 90 ml/min/1.73 m2) to < 31 ml/min/1.73 m2. We measured AGE-peptides, markers of endothelial dysfunction (von Willebrand factor, soluble E-selectin, plasminogen activator inhibitor-1, tissue-type plasminogen activator, soluble vascular cell adhesion molecule-1) and markers of inflammatory activity (soluble intercellular adhesion molecule-1, C-reactive protein, secretory phospholipase A2). We constructed composite endothelial dysfunction and inflammatory activity Z-scores using these markers., Results: AGE-peptides were independently related to creatinine clearance (standardized beta -0.55, 95% confidence interval (CI) -0.77 to -0.34, P < 0.001). AGE-peptides were not independently related to the individual markers of endothelial dysfunction and inflammation, nor to the composite endothelial dysfunction Z-score (standardized beta 0.08, 95% CI -0.14 to -0.30, P = 0.48) or the inflammatory activity Z-score (standardized beta -0.05, 95% CI -0.25 to -0.16, P = 0.66)., Conclusions: Plasma concentrations of AGE-peptides are associated with creatinine clearance but not with biochemical markers of endothelial dysfunction and inflammatory activity in non-diabetic patients over a wide range of renal function. This suggests that the atherogenic effects of AGE-peptides in individuals with renal functional impairment are not mediated by endothelial dysfunction or inflammatory activity as estimated by the markers used.

Mildly impaired renal function is associated with cardiovascular morbidity and mortality. There are indications that endothelial dysfunction and/or chronic inflammation, which play an important role in atherothrombosis, are present in early stages of renal insufficiency. This study investigated whether and to which extent endothelial dysfunction and inflammation were related to renal function and contributed to renal function-associated cardiovascular mortality in a population-based cohort (n = 613), aged 50 to 75 yr, that was followed with a median duration of 12.5 yr. During follow-up, 192 individuals died (67 of cardiovascular causes). At baseline, renal function was estimated with serum creatinine, the Cockcroft-Gault formula, and the Modification of Diet in Renal Disease equation of GFR (eGFR). Endothelial function was estimated by plasma von Willebrand factor, soluble vascular cell adhesion molecule-1, and the urinary albumin-creatinine ratio. Inflammatory activity was estimated by plasma C-reactive protein and soluble intercellular adhesion molecule-1. Renal function was mildly impaired (mean eGFR 68 +/- 12 ml/min per 1.73 m(2)) and independently associated with von Willebrand factor (standardized beta -0.09; 95% confidence interval [CI] -0.18 to -0.002; P < 0.05), soluble vascular cell adhesion molecule-1 (standardized beta -0.14; 95% CI -0.22 to -0.05; P < 0.01), and albumin-creatinine ratio (standardized beta -0.15; 95% CI -0.23 to -0.08; P < 0.001) but not with markers of inflammatory activity. Renal function was inversely associated with cardiovascular and all-cause mortality. The relative risk for cardiovascular mortality but not all-cause mortality associated with renal function decreased from 1.22 to 1.12 per 5 ml/min per 1.73 m(2) decrease of eGFR after adjustment for markers of endothelial dysfunction. In conclusion, endothelial dysfunction was related to renal function and contributed to the excess in cardiovascular mortality in this population-based cohort with mild renal insufficiency.

Background: Cardiovascular disease (CVD) is a frequent complication in chronic haemodialysis (HD) patients. Endothelial dysfunction, as measured by soluble cellular adhesion molecules (sCAM) and von Willebrand factor (vWf) in plasma, is an early manifestation of CVD. Today, it is unknown if, and to what extent, their levels are influenced by the type of dialyser., Methods: Four dialysers, low-flux cuprammonium (CU); high-flux and low-flux polysulfone and super-flux polyethersulfone, were compared in 15 chronic HD patients in a randomized cross-over fashion. sCAM and vWf were measured at baseline as well as after 4 weeks, and both intra-dialytical and after 24 h (t24 h). Twenty healthy subjects served as controls., Results: Baseline levels were considerably higher in chronic HD patients than in controls (soluble intercellular adhesion molecule-1: sICAM-1 732+/-216 vs 572+/-259 ng/ml, P = 0.06; soluble vascular cell adhesion molecule-1: sVCAM-1 1917+/-492 vs 1126+/-338 ng/ml, P<0.001; vWF: 205+/-55% vs 98+/-52%, P<0.001). After 4 weeks, no changes were observed. During and after HD, sCAM did not change, except in the case of CU (sICAM-1: 719+/-259 to 772+/-261 ng/ml, P = 0.04). CU induced a rise in vWF directly after HD (t4 h; from 188+/-48% to 255+/-92%, P<0.01), whereas all modalities induced a significant increase at t24 h (mean 228+/-54%, P = 0.02). The levels of sCAM and vWf appeared to be dependent on the individual patients rather than on the type of dialyser (explained variance by different patients: 66%-91%, P<0.001; by type of dialyser 0.4-1.2%)., Conclusions: Baseline levels of sCAM and vWf were markedly higher in chronic HD patients than in controls and did not change after 4 weeks with any dialyser. All membranes induced a marked rise in vWf at t24 h, whereas sICAM-1 increased only in the case of CU at t4 h. As sCAM showed no marked changes during HD with any other modality, our study suggests activation of blood cells rather than endothelial cells. As pre-dialysis levels of sCAM and vWf varied noticeably between individual patients, endothelial dysfunction seems to be far more dependent on patient-related factors than on the HD treatment itself.

Folic acid treatment decreases plasma total homocysteine concentrations in healthy subjects, but the effects on homocysteine metabolism are unknown. In the present study, we investigated the effect of 3 weeks of oral treatment with 5 mg of folic acid on one-carbon flux rates in 12 healthy subjects, using in vivo stable isotope methods. In addition, we determined the effect of folic acid on blood concentrations of amino acids which may have regulatory roles in homocysteine metabolism, i.e. homocysteine, AdoMet (S-adenosylmethionine), AdoHcy (S-adenosylhomocysteine), serine and glycine. Primed, continuous infusions with [2H3-methyl-1-13C]methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation and homocysteine trans-sulphuration. Metabolic homocysteine clearance was defined as the ratio of trans-sulphuration and plasma homocysteine level. Folic acid treatment increased the homocysteine remethylation rate by 59% [95% CI (confidence interval), 13-97%; P = 0.02] and methionine transmethylation rate by 20% (95% CI, 3-41%; P=0.03). Plasma total homocysteine concentration (-18%; 95% CI, -28 to -9%; P<0.01) and the serine/glycine ratio (-20%; 95% CI, -63 to -6%; P<0.01) decreased significantly, and the AdoMet/AdoHcy ratio (11%; 95% CI, 1-20%; P = 0.02) increased significantly. Changes in one-carbon flux rates did not correlate significantly with changes in plasma concentration of these amino acids. In conclusion, folic acid treatment lowered plasma homocysteine concentration and increased whole-body remethylation and transmethylation flux in healthy subjects.

Background: The pathogenesis of hyperhomocysteinemia in end-stage renal disease (ESRD) is unclear. Folic acid lowers, but does not normalize, the plasma homocysteine level in patients with ESRD, but its effect on whole body metabolism of homocysteine is unknown., Methods: We studied the effect of 3 weeks of oral treatment with 5 mg folic acid per day on homocysteine metabolism in six chronic hemodialysis patients and six healthy controls. Primed, continuous infusions with [(2)H(3)-methyl-1-(13)C] methionine were used to determine flux rates of methionine transmethylation, homocysteine remethylation, and homocysteine transsulfuration. Metabolic homocysteine clearance was defined as the ratio of transsulfuration and plasma homocysteine level., Results: Folic acid treatment lowered plasma homocysteine significantly by 39% (95% CI 5 to 73) in the ESRD group, but plasma homocysteine remained higher than baseline values in the control group. In ESRD patients, homocysteine remethylation and methionine transmethylation rate increased by 34% (95% CI 5 to 62) and 22% (95% CI 5 to 39), respectively (i.e., levels that were similar to the baseline values of the control group). Transsulfuration rate and metabolic homocysteine clearance were not significantly altered by folic acid treatment in both the ESRD and the control group., Conclusion: In ESRD patients, folic acid treatment lowers, but does not normalize plasma homocysteine, whereas homocysteine remethylation and methionine transmethylation increase to levels found in untreated healthy controls. These findings indicate a persistent, folate-independent, defect in metabolic homocysteine clearance in ESRD.

Hyperhomocysteinaemia almost invariably occurs in patients with end-stage renal disease (ESRD), but there is debate whether, within the group of ESRD patients, higher or lower plasma homocysteine concentrations are related to an increased risk of vascular disease. Homocysteine is thought to be vasculotoxic in high concentrations, but it may also lead to elevated levels of its precursor, S-adenosylhomocysteine (AdoHcy), which is a potent inhibitor of the transmethylation pathway, in which S-adenosylmethionine (AdoMet) donates its methyl group to a variety of acceptors. Impairment of this transmethylation pathway in ESRD patients has been suggested by high AdoHcy levels, decreased AdoMet/AdoHcy ratios, decreased protein repair requiring methyltransferases, and by DNA hypomethylation. Stable isotope techniques using labelled methionine have indeed demonstrated a decreased whole body transmethylation flux in ESRD patients. These studies have also shown that folic acid treatment is capable of restoring transmethylation rates to normal values. The remaining hyperhomocysteinaemia after folic acid treatment in ESRD is probably due to a persistent impairment of homocysteine clearance through transsulphuration. DNA hypomethylation with its concurrent alterations in gene expression is largely improved by folate treatment. The adverse effects of hyperhomocysteinaemia in ESRD may thus be related to impaired transmethylation. Normalisation of plasma homocysteine does not seem to be required to restore transmethylation to normal levels in ESRD patients.

Hyperhomocysteinemia is a risk factor for cardiovascular disease and occurs frequently in end-stage renal disease (ESRD), but its pathogenesis is poorly understood. We aimed to evaluate one-carbon flux rates of methionine and homocysteine (Hcy) in ESRD patients and healthy controls. Transmethylation (TM), remethylation (RM), and transsulfuration (TS), as well as Hcy clearance by TS (i.e., TS/plasma total Hcy concentration) and by RM (i.e., RM/plasma total Hcy concentration) were evaluated in relation to body composition, vitamins, and S-adenosylhomocysteine (AdoHcy) and S-adenosylmethionine (AdoMet) levels. After a fixed protein diet for 3 days, primed-continuous infusion of [(2)H(3)-methyl-1-(13)C]methionine was performed in the postabsorptive state in 12 hemodialysis patients and 16 healthy volunteers. Hcy clearance by TS (-80%, P < 0.001) and by RM (-77%, P < 0.001) in ESRD patients was decreased compared with healthy controls. The absolute flux rates of TM (-27%, P < 0.01) and RM (-28%, P = 0.02) were lower in the ESRD patients. After adjustment for age, TS was not significantly reduced. Whole blood AdoHcy was significantly elevated in ESRD and was a significant determinant of TM (standardized beta = -1.24, P = 0.01) and RM (standardized beta = -1.43, P = 0.03). In conclusion, patients with ESRD have impaired Hcy clearance by TS and RM. Elevated whole blood AdoHcy levels are associated with impaired RM and TM flux rates in these patients, and AdoHcy may be a key regulatory compound in one-carbon flux.

A patient who bred exotic turtles as a hobby presented with 2 episodes of severe diarrhea, the second of which was proven to be caused by turtle-associated salmonellosis that was contracted during treatment with a proton-pump inhibitor. The literature about reptile-associated salmonellosis is briefly reviewed.

This randomised double-blind, placebo-controlled, clinical trial investigated the effect of 3 months of treatment with calcium dobesilate on endothelium-dependent vasodilation, markers of endothelial function, blood pressure, and markers of oxidation in obese, male smokers. Vascular effects may depend on the type of vessel and we, therefore, investigated both smaller arteries, i.e. resistance arteries and small arterioles, and large conduit arteries. Vascular function was measured by acetylcholine- and sodium-nitroprusside-mediated vasodilation, and capillary recruitment, in the skin microcirculation; by forearm blood flow (FBF) responses to several agonists and to N-G-monomethyl L-arginine (L-NMMA) in the forearm vascular bed; by flow-mediated vasodilation in the brachial artery; and by determination of soluble levels of vascular cell adhesion molecule-1 (sVCAM-1), intercellular adhesion molecule-1 (sICAM-1) and E-selectin. Twenty-eight individuals received dobesilate and 24 placebo. No effect of calcium dobesilate on endothelial function, blood pressure or markers of oxidation was observed compared with placebo. The difference in acetylcholine-mediated vasodilation in the microcirculation was -52.1%-point (95% confidence interval -132.8 to 28.1); in sodium-nitroprusside-mediated vasodilation in the microcirculation, 2.6%-point (-95.1 to 100.2); in capillary recruitment, 2.5%-point (-6.8 to 11.7); in acetylcholine-induced increases in FBF (n=28), 23%-point (-173 to 126); in L-NMMA-induced reduction of basal FBF, -2.8%-point (-29.3 to 23.8); in flow-mediated vasodilation of the brachial artery, 0.3%-points (-2.7 to 3.3); in 24-h systolic blood pressure, 2.1 mmHg (-1.3 to 5.5); in soluble VCAM-1, 54 ng/ml (-8 to 115); in soluble ICAM-1, 9 ng/ml (-49 to 67); in sE-selectin, -17 ng/ml (-44 to 11); in ketocholesterol 5 nM (-17 to 26); and in oxidised LDL -1.6 U/l (-6.7 to 3.5). We have shown that endothelial function, blood pressure, and markers of oxidation were not affected by 3 months of treatment with calcium dobesilate in mildly obese, smoking men. Thus, our data provide no evidence of an effect on vascular function of calcium dobesilate in humans.

Background: Patients with end-stage renal disease (ESRD) as well as those with mild renal insufficiency are at increased risk for the development of cardiovascular disease, which cannot be attributed entirely to traditional risk factors. Endothelial dysfunction and chronic inflammatory activity, two important phenomena in atherogenesis, can be found in ESRD. At present, it is unclear whether endothelial dysfunction and chronic inflammatory activity are related to renal function in the pre-dialysis stage., Methods: In a cross-sectional, single-centre study, four groups of 20 subjects with renal function ranging from a normal, calculated creatinine clearance (>90 ml/min) to a pre-dialysis situation (<31 ml/min) were investigated. We measured markers of endothelial function [von Willebrand factor (vWf), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and E-selectin (ES)], and markers of inflammatory activity [secretory phospholipase A(2) (sPLA(2)) and C-reactive protein (CRP)]. Using these markers, composite endothelial function and inflammatory activity scores were constructed., Results: Creatinine clearance correlated with the endothelial function score (r=-0.43, P<0.001), the inflammatory activity score (r=-0.53, P<0.05), vWf (r=-0.54, P<0.001), sVCAM-1 (r=-0.50, P<0.001), sPLA(2) (r=-0.28, P<0.05), homocysteine (r=-0.61, P<0.001), age (r=-0.54, P<0.001) and blood pressure (r=-0.44, P<0.001). In multivariate analyses, creatinine clearance was an independent determinant of the endothelial function score (beta=-0.34, P=0.006), plasma vWf (beta=-0.37, P=0.022) and sICAM-1 (beta=-0.33, P=0.012). The relationship of creatinine clearance with sVCAM-1 and endothelial function score was not significant when plasma homocysteine was added to the model. Creatinine clearance was also a determinant of the inflammatory activity score (beta=-0.31, P=0.025) and sPLA(2) (beta=-0.32, P=0.024), although this was no longer significant after correction for systolic blood pressure., Conclusions: Renal dysfunction is associated with markers of endothelial dysfunction and inflammatory activity. Plasma homocysteine may be an intermediate factor in the relationship between endothelial dysfunction and renal function, while blood pressure may modulate the association between inflammatory activity and renal function.

With intravenous infusion of doubly-labeled [2H3C-1(-13)C-] methionine and stable isotope enrichments in plasma free methionine and carbon dioxide in breath air, whole body transmethylation, transsulfuration, and remethylation rates can be calculated. This technique demonstrated impaired recycling as the major disturbance to explain hyperhomocysteinemia in patients with end-stage renal failure, and can be used to optimize interventions with folate, B6, and B12 supplementation in this patient group. Intravenous infusion of [2,3,3-(2)H3] serine has also been applied to demonstrate the appearance of [2H2]- as well as [2H1]-methionine in plasma and protein, suggesting transfer of a one-carbon group from serine via 5,10-methylenetetrahydrofolate in human hepatocyte cytosol and mitochondria, respectively. In sheep, tissue free methionine enrichments after infusion of universally labeled [U-13C] methionine showed the highest remethylation activity in postmortem investigation of jejunum, liver, and kidney tissue samples, but no such activity in muscle and brain samples. Methods to quantitate one-carbon acceptor metabolism pathways and folate metabolism have recently become available.