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OBJECTIVE Clamp studies have shown that the absorption and action of rapid-acting insulin are faster with injection by a jet injector than with administration by conventional pen. To determine whether these pharmacokinetic changes also exist in patients with diabetes and benefit postprandial glucose control, we compared the pharmacologic profiles of insulin administration by jet injection versus conventional insulin pen after a standardized meal in patients with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS In a randomized, double-blind, double-dummy crossover study, 12 patients with type 1 diabetes and 12 patients with type 2 diabetes received insulin aspart either by jet injection or by conventional pen, in both cases followed by a standardized meal. Blood was sampled for 6 h for determination of glucose and insulin levels to calculate pharmacologic profiles. RESULTS Insulin administration by jet injection resulted in shorter time until peak plasma insulin level (51.3 ± 6.4 vs. 91.9 ± 10.2 min; P = 0.003) and reduced hyperglycemic burden during the first hour (154.3 ± 20.8 vs. 196.3 ± 18.4 mmol · min · L−1; P = 0.041) compared with conventional administration. Jet injection did not, however, significantly reduce the hyperglycemic burden during the 5-h period thereafter. There was no indication that the jet injector performed differently in patients with type 1 and type 2 diabetes. CONCLUSIONS The considerably more rapid insulin absorption after administration by jet injector translated to a significant if modest decrease in postprandial hyperglycemia in patients with type 1 and type 2 diabetes. The improved early postprandial glucose control may specifically benefit patients who have difficulty in limiting postprandial glucose excursions.

Item does not contain fulltext AIMS: Depression is common in people with diabetes, and related to higher HbA(1c) levels. Depression, however, is a heterogeneous construct that involves a variety of symptoms. As little is known about the associations of individual depressive symptoms with HbA(1c) , we explored these associations in outpatients with diabetes. METHODS: The study was conducted in three tertiary diabetes clinics in the Netherlands. At baseline, the presence of the nine depressive symptoms that are listed in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition was assessed with the nine-item Patient Health Questionnaire (PHQ-9). At baseline and after a 1-year follow-up, HbA(1c) was derived from the medical charts. RESULTS: A total of 288 out of 646 subjects with diabetes (45%) reported one or more depressive symptom(s). Depressed mood (beta = 0.11, P = 0.005), sleeping difficulties (beta = 0.16, P < 0.001), appetite problems (beta = 0.15, P < 0.001) and suicidal ideation (beta = 0.14, P = 0.001) were significantly related to higher baseline HbA(1c) values. Furthermore, depressed mood (beta = 0.09, P = 0.03) sleeping difficulties (beta = 0.12, P = 0.004), appetite problems (beta = 0.11, P = 0.01) and psychomotor agitation/retardation (beta = 0.09, P = 0.04) were significantly related to higher HbA(1c) values at 1-year follow-up. Associations were more pronounced in Type 1 diabetes than in Type 2 diabetes. None of the depressive symptoms were related to change in HbA(1c) over time, except suicidal ideation. CONCLUSION: In people with diabetes, several individual depressive symptoms were related to higher HbA(1c) levels. These associations persisted over time. More research is needed to investigate potential mechanistic pathways.

Item does not contain fulltext BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) are typically overweight and have an increased liver fat content (LFAT). High LFAT may be explained by an increased efflux of free fatty acids from the adipose tissue, which is partly instigated by inflammatory changes. This would imply an association between inflammatory features of the adipose tissue and liver fat content. OBJECTIVE: To analyse associations between inflammatory features of the adipose tissue and liver fat content. DESIGN: A cross-sectional study. PATIENTS: Twenty-seven obese patients with insulin-treated T2DM were studied. MEASUREMENTS: LFAT content was measured by proton magnetic resonance spectroscopy. A subcutaneous (sc) fat biopsy was obtained to determine morphology and protein levels within adipose tissue. In addition to fat cell size, the percentage of macrophages and the presence of crown-like structures (CLSs) within sc fat were assessed by CD68-immunohistochemical staining. RESULTS: Mean LFAT percentage was 11.1 +/- 1.7% (range: 0.75-32.9%); 63% of the patients were diagnosed with an elevated LFAT (upper range of normal

Item does not contain fulltext Large defects in congenital diaphragmatic hernia are closed by patch repair, which is associated with a high complication risk and reherniation rate. New treatment modalities are warranted. We evaluated the feasibility of using an acellular biodegradable collagen bioscaffold for a regenerative medicine approach to close a surgically created diaphragmatic defect in a rat model. Scaffold degradation, cellular ingrowth and regeneration of the diaphragm were studied. In 25 rats, a subcostal incision was made and one third of the right hemidiaphragm was resected. Crosslinked porous type I collagen scaffolds (O ~ 14 mm) were sutured into the lesion. Rats were sacrificed at 2, 4, 8, 12 or 24 weeks after scaffold implantation. Implants were evaluated macroscopically and (immuno)histologically. Survival after surgery was 88% with no evidence of reherniation. Histological examination showed that the collagen scaffold degraded slowly and new collagen, elastin and mesothelium were deposited. Blood vessels were observed primarily at the outer borders of the scaffold; their number gradually increased in time. Muscle fibres were found on the scaffold covering up to 10% of the defect. Macroscopically, adhesion of the scaffold to the liver was observed. Use of a collagen scaffold to close a surgically created diaphragmatic defect is feasible, with evidence of new tissue formation. The use of crosslinked collagen scaffolds allows targeted modification; e.g. addition of growth factors to further stimulate growth of muscle cells. Copyright (c) 2012 John Wiley & Sons, Ltd.

IntroductionReduced testosterone levels are frequently observed in obese men. Increased aromatase activity may be an etiological factor.ObjectiveIn this study, we evaluate the clinical effects of aromatase inhibition in obesity-related hypogonadotropic hypotestosteronemia (OrHH).MethodsDouble-blind, placebo-controlled, 6-month trial in 42 obese men with a BMI >35 kg/m2, and a serum total testosterone EndpointsPsychological function, body composition, exercise capacity, and glucose, lipid, and bone metabolism.ResultsThirty-nine patients completed the study according to protocol. Letrozole decreased serum estradiol from 119.1±10.1 to 59.2±6.1 pmol/l (PPPConclusionDespite a marked rise in serum testosterone, low-dose aromatase inhibition had no somatic or psychological effects in men with OrHH.

Item does not contain fulltext OBJECTIVE: Parents and health professionals believe that recurrent respiratory tract infections (RRTI) have a large impact on children with Down syndrome (DS). We studied the relation between parent-reported RRTI and development, behaviour and health-related quality of life (HRQoL) in 8-year-old children with DS. METHOD: During a 3-year period, 325 children with DS were recruited for inclusion in this observational study. Parents were asked to fill in the Child Behavior Checklist and TNO-AZL Children's Quality of Life Parent Form. A psychological assistant administrated the McCarthy Scales of Children's Abilities. The children were divided into a group with presence of RRTI (RRTI (+) ) and a group without RRTI (RRTI (-) ), on the basis of parental report. Linear regression analyses were performed to assess the effect of RRTI, while correcting for the influence of confounders. RESULTS: Compared with RRTI (-) children (n = 176), RRTI (+) children (n = 149, 46%) showed decreased mental and motor development (mean developmental age 3.67 vs. 4.08 years), more behavioural problems and lower scores on most HRQoL scales (P < 0.05). Moreover, school enrolment is less favourable in RRTI (+) children. CONCLUSION: In 8-year-olds with DS, the children with parent-reported RRTI show more delayed development, more behavioural problems and lower HRQoL compared with the children without RRTI. Although this association does not prove a causal relationship, further studies should focus on this, because RRTI are potentially preventable. 01 november 2013

Item does not contain fulltext Expansion of adipose tissue mass, predominantly in the visceral depot, strongly associates with the development of metabolic complications that are often observed in obesity. In addition, in obesity, an increased prevalence of nonalcoholic fatty liver disease and reduced cardiorespiratory fitness are observed. However, not all obese individuals develop metabolic abnormalities. To better understand the molecular mechanisms that predispose obese humans to the development of metabolic diseases, comparing the metabolically healthy obese (MHO) vs an unhealthy obese phenotype (MUO) may be of great value. A new study by Esser et al (DOI: 10.1007/s00125-013-3023-9 ) now provides important evidence that the MHO phenotype is associated with a lower activation of the NOD-like receptor family pyrin domain containing-3 (NLPR3) inflammasome in macrophages of visceral adipose tissue and a more favourable inflammatory profile as compared with the MUO phenotype. This finding could promote novel studies in humans to decipher stimuli and mechanisms leading to increased inflammasome activity, not only in adipose tissue, but also in other organs that are involved in the regulation of metabolism.

Item does not contain fulltext MEPs and CMAPs as prognostic tools for spina bifida. AIM: The aim of this prospective study was to determine the prognostic value of neurophysiological investigations compared to clinical neurological examination in infants with spina bifida. METHODS: Thirty-six neonates born with spina bifida between 2002 and 2007 were evaluated and followed for 2 years. Lumbar motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were obtained at the median age of 2 days old before surgical closure of the spinal anomaly. MEPs were recorded from the quadriceps femoris, tibialis anterior, and gastrocnemius muscles and CMAPs from the latter two muscles. Areas under the curve and latencies of the MEPs and CMAPs were measured. Clinical neurological outcome at the age of 2 years was described using Muscle Function Classes (MFCs) and ambulation status. RESULTS: The areas under the curve of MEPs and CMAPs in the legs were associated with lower neonatal levels of motor and sensory impairment. Better muscle function class of the lower limbs at 2 years of age was associated with larger MEP and CMAP areas of the gastrocnemius and tibialis anterior muscles at neonatal age. DISCUSSION: MEPs and CMAPs of the gastrocnemius and tibialis anterior muscles are of prognostic value for clinical neurological outcome in neonates born with spina bifida.

Item does not contain fulltext INTRODUCTION: In this study we describe a protocol for quantitative ultrasound of facial muscles (procerus, zygomaticus major, levator labii superior, depressor anguli oris, mentalis, orbicularis oris pars labialis, orbicularis oris pars marginalis). Methods: Muscle thickness (MT) and echo intensity (EI) were measured in 12 healthy subjects and a myotonic dystrophy type 1 patient. Results: MTs ranged from 0.15 to 0.30 mm, except for the procerus muscle (0.06 mm). EIs ranged from 1 to 34, except for the procerus muscle. MT reproducibility was fair for the orbicularis oris pars labialis, excellent for the procerus and levator labii, and good for the other muscles. The myotonic dystrophy type 1 patient showed high EIs, outside the range in healthy subjects in 6 of the 7 muscles. MT was lower than the range seen in healthy subjects in 4 muscles. Conclusion: Quantitative muscle ultrasound of the facial muscles is feasible and shows moderate to excellent reproducibility. Muscle Nerve 48: 375-380, 2013.

Item does not contain fulltext Context: Corticotroph pituitary adenomas often highly express the dopamine 2 receptor (D2R) and somatostatin receptor subtype 5 (sst5). The sst2 expression is relatively low, likely resulting from downregulating effects of high cortisol levels. This may explain why the sst2-preferring somatostatin analog octreotide, compared with the multi-receptor-targeting somatostatin analog pasireotide, is generally ineffective in Cushing's disease. Objective: Our objective was to compare sst and D2R expression levels between adenomas from patients with elevated and normalized preoperative urinary free cortisol excretion. Patients and Design: Corticotroph adenoma tissue was examined from patients from group 1 (n = 22; elevated preoperative urinary free cortisol) and group 2 (n = 11; mean duration of preoperative normocortisolism 10 weeks). Somatotroph adenoma tissue from 10 acromegalic patients was examined to compare receptor expression profiles. Main Outcome Measures: We evaluated receptor mRNA and protein expression levels and effects of octreotide, pasireotide, and cabergoline on ACTH secretion by cultured human corticotroph adenoma cells. Results: The sst2 mRNA expression in group 2 was 10-fold higher than in group 1 (P < .01), even comparable to that in somatotroph adenomas. There were no statistically significant differences in sst5 and D2R mRNA expression or in sst2, sst5, and D2R protein expression between both groups of corticotroph adenomas. In responders, octreotide (n = 2 out of 4; -30.5% +/- 10.4%) was less potent than pasireotide (n = 5 out of 6; -47.0% +/- 4.2%) and cabergoline (n = 3 out of 4; -41.9% +/- 3.1%) with respect to inhibition of ACTH secretion by adenomas from group 2. Conclusions: After achieving normocortisolism induced by medical therapy, cortisol-mediated sst2 downregulation on corticotroph adenomas appears to be a reversible process at the mRNA but not at the protein level. Octreotide remains less potent than pasireotide and cabergoline with respect to in vitro inhibition of ACTH secretion. Whether sustained normocortisolism induced by medical therapy induces re-expression of functional sst2 protein in corticotroph adenomas and whether this increases the ACTH-lowering potency of octreotide remains to be established. 01 december 2013

Item does not contain fulltext Mid-aortic syndrome is characterized by narrowing of the abdominal aorta, usually with the involvement of renal arteries and other visceral branches. The combination of the presence of an abdominal bruit, diminished or absent pulsations of the lower extremities, and a blood pressure discrepancy between upper and lower extremities is the classic triad associated with mid-aortic syndrome. However, it has a wide variety of clinical symptoms, and awareness of the variable presentation can lead to early diagnosis of the vascular anomaly. We report three cases presenting at three different stages of this disease, such as hydrops fetalis, refractory hypertension, and intracerebral bleeding. In conclusion, these cases highlight the importance of blood pressure measurements in all patients and accurate physical examination for early recognition of a mid-aortic syndrome. 01 maart 2013

Item does not contain fulltext Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism. 01 december 2013

Item does not contain fulltext BACKGROUND: /st> Asthma is a common disease in children and often develops early in life. This multicentre retrospective case series describe the use and effectiveness of sevoflurane inhalation therapy in a series of children with severe asthma in the paediatric intensive care unit (PICU). METHODS: /st> Seven children ranging from 4 to 13 yr of age admitted to the PICU of two tertiary care hospitals in the Netherlands were included. They all were admitted with the diag-nosis of severe asthma requiring invasive mechanical ventilation and were treated with sevoflurane inhalation therapy. RESULTS: /st> The median (range) Pco2 level at the start, after 2 h, and at the end of sevoflurane treatment were 14 (5.1-24.8), 9.8 (5.4-17.0), and 6.2 (4.5-11.4) kPa (P=0.05) while the median (range) pH was 7.02 (6.97-7.36), 7.18 (7.04-7.35), and 7.43 (7.15-7.47) kPa (P=0.01), respectively. The median (range) peak pressure values declined from 30 (23-56) to 20.4 (14-33) cm H2O (P=0.03). No severe adverse effects besides hypotension, with sufficient response to norepinephrine treatment, were seen. CONCLUSIONS: /st> Sevoflurane inhalation corrects high levels of Pco2 and provides clinical improvement in mechanically ventilated children with life-threatening asthma who fail to respond to conventional treatment. 01 december 2013

Item does not contain fulltext PURPOSE: Brain MR imaging is essential in the assessment of Chiari II malformation in clinical and research settings concerning spina bifida. However, the interpretation of MR images of the malformation is not always straightforward. Morphometric analyses of the extent of Chiari II malformation may improve the assessment. In an attempt to select appropriate morphometric measures for this purpose, we investigated the interobserver reliability and diagnostic performance of several morphometric measures of Chiari II malformation on MR images. METHODS: Brain MR images of 79 children [26 with open spinal dysraphism, 17 with closed spinal dysraphism, and 36 without spinal dysraphism; mean age 10.6 (SD 3.2; range, 6-16) years] were evaluated. All children had been assessed for Chiari II malformation (defined as cerebellar herniation in combination with open spinal dysraphism; n = 23). Three observers blindly and independently reviewed the MR images for 21 measures of the cerebellum, brainstem, and posterior fossa in three planes. The interobserver reliability was assessed by an agreement index (AI = 1 - RRE) and the diagnostic performance by receiver operating characteristic analyses. RESULTS: Reliability was good for most measures, except for the degree of herniation of the vermis and tonsil. Most values differed statistically significantly between children with and without Chiari II malformation. The measures mamillopontine distance and cerebellar width showed excellent diagnostic performance. CONCLUSIONS: Morphometric measures may reliably quantify the morphological distortions of Chiari II malformation on MR images and provide additional tools to assess the severity of Chiari II malformation in clinical and research settings. 01 juli 2012

Item does not contain fulltext The peroxisome proliferator activated receptor-alpha (PPARalpha) is a major transcriptional regulator of lipid metabolism in liver and represents the molecular target for hypolipidemic fibrate drugs. Effects of PPARalpha on lipid metabolism are partially mediated by circulating proteins such as FGF21 and ANGPTL4. The present study was undertaken to screen for and identify circulating proteins produced by human liver that are under the control of PPARalpha. Toward that aim, primary human hepatocytes were treated with the synthetic PPARalpha agonist Wy-14643 and whole genome expression data selected for secreted proteins. Expression of FGF21, ANGPTL4, and mannose-binding lectin (MBL), a soluble mediator of innate immunity and primary component of the lectin branch of the complement system, was markedly upregulated by Wy-14643 in primary human hepatocytes. Mice express two MBL isomers, Mbl1 and Mbl2. Mbl1 mRNA was weakly induced by Wy-14643 in primary mouse hepatocytes and remained unaltered by Wy-14643 in mouse liver. Mbl2 mRNA was unchanged by Wy-14643 in primary mouse hepatocytes and was strongly reduced by Wy-14643 in mouse liver. Remarkably, plasma Mbl1 levels were increased by chronic PPARalpha activation in lean and obese mice. Importantly, in two independent clinical trials, treatment with the PPARalpha agonist fenofibrate at 200 mg/day for 6 wk and 3 mo increased plasma MBL levels by 73 (P = 0.0016) and 86% (P = 0.017), respectively. It is concluded that hepatocyte gene expression and plasma levels of MBL are stimulated by PPARalpha and fenofibrate in humans, linking PPARalpha to regulation of innate immunity and complement activation in humans and suggesting a possible role of MBL in lipid metabolism.

Item does not contain fulltext AIMS: To determine the baseline characteristics and glucose-lowering therapies associated with weight change among patients with type 2 diabetes. METHODS: Eleven thousand one hundred and forty participants in the ADVANCE trial were randomly assigned to an intensive [aiming for a haemoglobin A1c (HbA1c)

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Item does not contain fulltext A growing body of evidence suggests that cytokines of the interleukin-1 (IL-1) family, particularly IL-1beta but also IL-1Ra and IL-18, are involved in obesity-associated inflammation. IL-1beta is produced via cleavage of pro-IL-1beta by caspase-1, which in turn is activated by a multiprotein complex called the inflammasome. The components of the NLRP3 inflammasome are involved in sensing obesity-associated danger signals, both in mice and in human (obese) subjects, with caspase-1 seemingly the most crucial regulator. Autophagy is upregulated in obesity and may function as a mechanism to control IL-1beta gene expression in adipose tissue to mitigate chronic inflammation. All these mechanisms are operative in human adipose tissue and appear to be more pronounced in human visceral compared to subcutaneous tissue. In animal studies, blocking caspase-1 activity results in decreased weight gain, decreased inflammation, and improved insulin sensitivity. Human intervention studies with IL-1Ra (anakinra) have reported beneficial effects in patients with diabetes, yet without significant changes in insulin sensitivity. Clearly, the IL-1 family of cytokines, especially IL-1beta, plays an important role in obesity-associated inflammation and insulin resistance and may represent a therapeutic target to reverse the detrimental metabolic consequences of obesity. 01 september 2012

Contains fulltext : 108806.pdf (Publisher’s version ) (Open Access) Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased iNKT cell numbers and marginal effects of iNKT cell depletion on insulin resistance under high-fat diet conditions. Here, we focused on the role of iNKT cells under normal conditions. We showed that iNKT cell-deficient mice on a low-fat diet, considered a normal diet for mice, displayed a distinctive insulin resistance phenotype without overt adipose tissue inflammation. Insulin resistance was characterized by adipocyte dysfunction, including adipocyte hypertrophy, increased leptin, and decreased adiponectin levels. The lack of liver abnormalities in CD1d-null mice together with the enrichment of CD1d-restricted iNKT cells in both mouse and human adipose tissue indicated a specific role for adipose tissue-resident iNKT cells in the development of insulin resistance. Strikingly, iNKT cell function was directly modulated by adipocytes, which acted as lipid antigen-presenting cells in a CD1d-mediated fashion. Based on these findings, we propose that, especially under low-fat diet conditions, adipose tissue-resident iNKT cells maintain healthy adipose tissue through direct interplay with adipocytes and prevent insulin resistance.

Item does not contain fulltext Immunophenotyping of blood lymphocyte subpopulations is an important tool in the diagnosis of immunological and haematological diseases. Paediatric age-matched reference values have been determined for the major lymphocyte populations, but reliable reference values for the more recently described T lymphocyte subpopulations, like different types of memory T lymphocytes, recent thymic emigrants, regulatory T cells and CXCR5(+) helper T lymphocytes, are not sufficiently available yet. We determined reference values for the absolute and relative sizes of T lymphocyte subpopulations in healthy children using the lysed whole blood method, which is most often used in diagnostic procedures. When the absolute numbers of some or all T lymphocyte subpopulations fall outside these reference ranges, this may indicate disease. The reference values show the course of T lymphocyte development in healthy children. Absolute T lymphocyte numbers increase 1.4-fold during the first months of life, and after 9-15 months, they decrease threefold to adult values; this is mainly caused by the expansion of recent thymic emigrants and naive cells. Helper and cytotoxic T lymphocytes show the same pattern. Regulatory T cells increase in the first 5 months of life and then gradually decrease to adult values, although the absolute numbers remain small. The relative number of CXCR5(+) cells within the CD4(+) CD45RO(+) T lymphocytes increases during the first 6 months of life and then remains more or less stable around 20%. 01 april 2012

Item does not contain fulltext BACKGROUND AND OBJECTIVES: One of the advantages of ultrasound-guided peripheral nerve block is that visualization of local anesthetic spread allows for a reduction in dose. However, little is known about the effect of dose reduction on sensory and motor block duration. The purpose of the present study was to compare the duration of sensory and motor axillary brachial plexus block (ABPB) with 15 or 40 mL mepivacaine 1.5%. METHODS: Thirty patients were randomly allocated to receive ultrasound-guided ABPB with either 15 (group 15 mL, n = 15) or 40 mL (group 40 mL, n = 15) mepivacaine 1.5%. Onset, efficacy, and duration of sensory and motor block were compared. RESULTS: Two patients in group 15 mL needed an additional rescue block before surgery and were excluded from subsequent analysis. The overall median duration of sensory and motor block was significantly shorter in group 15 mL (225 [148-265] mins vs 271 [210-401] mins and 217 [144-250] mins vs 269 [210-401] mins, respectively; P < 0.01). Duration of sensory and motor block of individual nerves was significantly shorter in group 15 mL (20%-40% reduction for sensory and 18%-37% for motor block). Time to first request of postoperative analgesia was also significantly reduced in group 15 mL (163 [SD, 39] vs 235 [SD, 59] mins, respectively, P < 0.05). There were no differences in the other block characteristics. CONCLUSIONS: In ABPB with mepivacaine 1.5%, reducing the dose from 40 mL to 15 mL (62.5%) shortens the overall duration of sensory and motor block by approximately 17% to 19%, reduces sensory and motor block duration of individual nerves by 18% to 40%, and decreases the time to first request of postoperative analgesia by approximately 30%.

OBJECTIVE Insulin administered by jet injectors is dispensed over a larger subcutaneous area than insulin injected with a syringe, which may facilitate a more rapid absorption. This study compared the pharmacologic profile of administration of insulin aspart by jet injection to that by conventional insulin pen. RESEARCH DESIGN AND METHODS Euglycemic glucose clamp tests were performed in 18 healthy volunteers after subcutaneous administration of 0.2 units/kg body wt of aspart, either administered by jet injection or by conventional pen, using a randomized, double-blind, double-dummy, cross over study design. Pharmacodynamic and pharmacokinetic profiles were derived from the glucose infusion rate (GIR) needed to maintain euglycemia and from plasma insulin levels, respectively. RESULTS The time to maximal GIR was significantly shorter when insulin was injected with the jet injector compared with conventional pen administration (51 ± 3 vs. 105 ± 11 min, P < 0.0001). The time to peak insulin concentration was similarly reduced (31 ± 3 vs. 64 ± 6 min, P < 0.0001) and peak insulin concentrations were increased (108 ± 13 vs. 79 ± 7 mU/L, P = 0.01) when insulin was injected by jet injection compared with conventional pen injection. Jet injector insulin administration reduced the time to 50% glucose disposal by ∼40 min (P < 0.0001). There were no differences in maximal GIR, total insulin absorption, or total insulin action between the two devices. CONCLUSIONS Administration of insulin aspart by jet injection enhances insulin absorption and reduces the duration of glucose-lowering action. This profile resembles more closely the pattern of endogenous insulin secretion and may help to achieve better meal insulin coverage and correction of postprandial glucose excursions.

BackgroundDepression increases the risk of subsequent vascular events in both cardiac and non-cardiac patients. Atherosclerosis, the underlying process leading to vascular events, has been associated with depression. This association, however, may be confounded by the somatic-affective symptoms being a consequence of cardiovascular disease. While taking into account the differentiation between somatic-affective and cognitive-affective symptoms of depression, we examined the association between depression and atherosclerosis in a community-based sample.MethodIn 1261 participants of the Nijmegen Biomedical Study (NBS), aged 50–70 years and free of stroke and dementia, we measured the intima–media thickness (IMT) of the carotid artery as a measure of atherosclerosis and we assessed depressive symptoms using the Beck Depression Inventory (BDI). Principal components analysis (PCA) of the BDI items yielded two factors, representing a cognitive-affective and a somatic-affective symptom cluster. While correcting for confounders, we used separate multiple regression analyses to test the BDI sum score and both depression symptom clusters.ResultsWe found a significant correlation between the BDI sum score and the IMT. Cognitive-affective, but not somatic-affective, symptoms were also associated with the IMT. When we stratified for coronary artery disease (CAD), the somatic-affective symptom cluster correlated significantly with depression in both patients with and patients without CAD.ConclusionsThe association between depressive symptoms and atherosclerosis is explained by the somatic-affective symptom cluster of depression. Subclinical vascular disease thus may inflate depressive symptom scores and may explain why treatment of depression in cardiac patients hardly affects vascular outcome.

Contains fulltext : 96636.pdf (Publisher’s version ) (Closed access) Despite the theoretical benefits, angiotensin II type 1 receptor antagonists seem to enhance rather than reduce morbidity and mortality after myocardial infarction compared with angiotensin-converting enzyme inhibitors. This may result from unopposed angiotensin II type 2 receptor stimulation, which is associated with enhanced apoptotic cell death and increased infarct size. We studied whether the clinical effectiveness of irbesartan is hampered by enhanced apoptotic activity, detected by exposition of phosphatidylserines, during ischemia and reperfusion in humans in vivo. Twenty healthy male volunteers were randomized to a 1-week treatment with irbesartan (300 mg/d) or placebo in a double-blind fashion. After treatment, all participants underwent 10 minutes of ischemic exercise of the nondominant forearm. Upon reperfusion, Tc-99m-labeled Annexin A5 was administered, and 1 and 4 hours afterward, both hands were scanned using a gamma camera. Targeting of annexin A5, expressed as the percentage difference in radioactivity in the area of interest (thenar muscle) between experimental and control hand, did not differ between participants treated with irbesartan or placebo. Therefore, irbesartan does not enhance phosphatidylserine exposition in humans in vivo. The results of this study do not support enhanced apoptotic activity after treatment with irbesartan in a setting of ischemia and reperfusion.

Contains fulltext : 97193.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Macrophages are key players in atherogenesis because of their properties to form foam cells that produce a large variety of pro-inflammatory mediators. We addressed the potency of phenotypic different macrophages to accumulate oxidized LDL. METHODS AND RESULTS: Surprisingly, anti-inflammatory M2 macrophages but not pro-inflammatory M1 macrophages rapidly accumulated oxidized LDL. Simultaneously, expression of Kruppel-like factor 2, a nuclear transcription factor known to suppress inflammation in endothelial cells and monocytes, decreased and the functional phenotype of M2 macrophages shifted towards a pro-inflammatory profile, characterized by higher production of IL-6, IL-8 and MCP-1 and lower expression of IL-10 upon stimulation with LPS. In contrast, Kruppel-like factor 2 expression and the phenotype of M1 macrophages remained largely unchanged upon oxidized LDL exposure. Downregulation of Kruppel-like factor 2 expression of M2 macrophages using siRNA technology led to a significant increase of LPS-induced MCP-1 secretion. CONCLUSIONS: We show that (1) anti-inflammatory M2 macrophages are more susceptible to foam cell formation than pro-inflammatory M1 macrophages, (2) exposure to oxidized LDL renders M2 macrophages pro-inflammatory, and (3) Kruppel-like factor 2 is involved in the enhanced secretion of MCP-1 by M2 macrophages loaded with oxidized LDL. The phenotype switch of M2 macrophages from an anti- to a pro-inflammatory profile may play an important role in pathogenesis of atherosclerosis, and could represent a novel therapeutic target.

Contains fulltext : 95722.pdf (Publisher’s version ) (Open Access) The prevalence and spread of azole resistance in clinical Aspergillus fumigatus isolates in the Netherlands are currently unknown. Therefore, we performed a prospective nationwide multicenter surveillance study to determine the effects of resistance on patient management strategies and public health. From June 2007 through January 2009, all clinical Aspergillus spp. isolates were screened for itraconazole resistance. In total, 2,062 isolates from 1,385 patients were screened; the prevalence of itraconazole resistance in A. fumigatus in our patient cohort was 5.3% (range 0.8%-9.5%). Patients with a hematologic or oncologic disease were more likely to harbor an azole-resistant isolate than were other patient groups (p

Contains fulltext : 96412.pdf (Publisher’s version ) (Closed access) In the concentration range that is normally achieved in humans, e.g., after the drinking of coffee or in patients treated with theophylline, the cardiovascular effects of methylxanthines are primarily due to antagonism of adenosine A(1) and A(2) receptors. Inhibition of phosphodiesterases or mobilization of intracellular calcium requires much higher concentrations. In conscious humans, acute exposure to caffeine results in an increase in blood pressure by an increased total peripheral resistance, and a slight decrease in heart rate. This overall hemodynamic response is composed of direct effects of caffeine on vascular tone, on myocardial contractility and conduction, and on the sympathetic nervous system. Caffeine is the most widely consumed methylxanthine, mainly derived from coffee intake. Regular coffee consumption can affect various traditional cardiovascular risk factors, including a slight increase in blood pressure, an increase in plasma cholesterol and homocysteine levels, and a reduced incidence of type 2 diabetes mellitus. Although most prospective studies have not reported an association between coffee consumption and coronary heart disease, these findings do not exclude that the acute hemodynamic and neurohumoral effects of coffee consumption could have an adverse effect in selected patient groups who are more vulnerable for these effects, based on their genetic profile or medication use.

Contains fulltext : 96423.pdf (Publisher’s version ) (Closed access) AIMS/HYPOTHESIS: Homozygosity for glycine at codon 16 (GlyGly) of the beta(2)-adrenergic receptor may alter receptor sensitivity upon chronic stimulation and has been implicated in the pathogenesis of hypoglycaemia unawareness. We compared the effect of antecedent hypoglycaemia on beta(2)-adrenergic receptor sensitivity between GlyGly participants and those with arginine 16 homozygosity (ArgArg) for the beta(2)-adrenergic receptor. METHODS: We enrolled 16 healthy participants, who were either GlyGly (n = 8) or ArgArg (n = 8). They participated randomly in two 2 day experiments. Day 1 consisted of two 2-h hyperinsulinaemic hypoglycaemic (2.8 mmol/l) or euglycaemic (4.8 mmol/l) glucose clamps. On day 2, we measured the forearm vasodilator response to the beta(2)-adrenergic receptor agonist salbutamol and the dose of isoprenaline required to increase the heart rate by 25 bpm (IC(25)). RESULTS: The vasodilator response to salbutamol tended to be greater after antecedent hypoglycaemia than after euglycaemia (p = 0.078), consistent with increased beta(2)-adrenergic receptor sensitivity. This effect was driven by a significant increase in beta(2)-adrenergic receptor sensitivity following hypoglycaemia compared with euglycaemia in ArgArg participants (p = 0.019), whereas no such effect was observed in the GlyGly participants. Antecedent hypoglycaemia tended to decrease the IC(25) in ArgArg participants, whereas the reverse occurred in the GlyGly participants (GlyGly vs ArgArg group p = 0.047). CONCLUSION/INTERPRETATION: Antecedent hypoglycaemia did not affect beta(2)-adrenergic receptor sensitivity in healthy GlyGly participants, but increased it in ArgArg participants. If these results also hold for participants with type 1 diabetes, such an increase in beta(2)-adrenergic receptor sensitivity may potentially reduce the risk of repeated hypoglycaemia and the subsequent development of hypoglycaemia unawareness in ArgArg diabetic participants. TRIAL REGISTRATION: ClinicalTrials.gov NCT00160056.

Item does not contain fulltext AIMS/HYPOTHESIS: The aim of this study was to test the effectiveness of a screening procedure for depression (SCR) vs care as usual (CAU) in outpatients with diabetes. The primary outcome measured was depression score and the secondary outcomes were mental healthcare consumption, diabetes-distress and HbA(1c). MATERIALS AND METHODS: In a multicentre parallel randomised controlled trial, 223 outpatients with diabetes, who had an elevated depression score, were randomly assigned to SCR (n = 116) or CAU (n = 107), using computer generated numbers. SCR-patients were invited for a Composite International Diagnostic Interview (CIDI) to diagnose depression and/or anxiety (interviewers were not blinded for group assignment). As part of the intervention, patients and their physicians were informed of the outcome of the CIDI in a letter and provided with treatment advice. At baseline and 6 month follow-up, depression and diabetes-distress were measured using the Centre for Epidemiologic Studies Depression Scale (CES-D) and the Problem Areas in Diabetes survey (PAID). HbA(1c) levels were obtained from medical charts. RESULTS: Mean CES-D depression scores decreased from baseline to 6 months in both groups (24 +/- 8 to 21 +/- 8 [CAU] and 26 +/- 7 to 22 +/- 10 [SCR] respectively [p < 0.001]), with no significant differences between groups. Neither diabetes-distress nor HbA(1c) changed significantly within and between groups. The percentage of patients receiving mental healthcare increased in the SCR group from 20% to 28%, compared with 15% to 18% in the CAU group. CONCLUSIONS/INTERPRETATION: Depression screening with written feedback to patient and physician does not improve depression scores and has a limited impact on mental healthcare utilisation, compared with CAU. It appears that more intensive depression management is required to improve depression outcomes in patients with diabetes.

Item does not contain fulltext BACKGROUND: Ultrasound is a non-invasive method to quantitatively measure various muscle parameters. Purpose of this study was to assess the feasibility of ultrasound of lower leg and foot muscles and to obtain reference values for muscle thickness (MT) and echo intensity (EI). METHODS: Ultrasound measurements of leg and foot muscles were performed in 60 healthy adults. MT and EI were quantitatively determined for the abductor hallucis (AH), extensor digitorum brevis (EDB), extensor hallucis longus (EHL) and peroneus longus (PER) muscles. Influence of age, height, weight and sex was determined using a multiple linear regression analysis. RESULTS: All muscles except the AH could easily be visualized with ultrasound. EI tended to be increased above 60 years and MT was significantly higher in men compared to women, necessitating age- and sex-dependent reference values. CONCLUSIONS: This study shows that muscle ultrasound is capable of visualizing lower leg and foot muscles and reference values for MT and EI can be obtained. Future research will focus on the use of these reference values to evaluate muscle abnormalities caused by neuromuscular disorders like hereditary motor and sensory neuropathy.

Item does not contain fulltext We prospectively investigated the diagnostic accuracy and potential pitfalls of dynamic muscle ultrasound in the detection of fibrillations. The presence of fibrillations on both electromyography (EMG) and ultrasound was evaluated in 102 muscles of 38 patients with suspected fibrillation potentials, based on history and physical examination. Sensitivity and specificity were calculated. False-positive and false-negative results are described to identify pitfalls. Ultrasound detected fibrillations with a sensitivity of 45% and a specificity of 66%. Specificity improved to 85% when measurements were evaluated online. Proximal muscles showed higher sensitivities (63%) than distal muscles (33%). Ultrasound currently has a poor sensitivity and moderate specificity for detecting fibrillations. Several pitfalls were identified that, when avoided, could help improve diagnostic accuracy. Ensuring a distal limb temperature of at least 34 degrees C and identifying external movement artifacts as well as voluntary contractions can improve efficacy and open the way for diagnostic application of this technique.

Item does not contain fulltext BACKGROUND: The 24- and 48-hour tetrahydrobiopterin (BH4) loading test (BLT) performed at a minimum baseline phenylalanine concentration of 400 mumol/l is commonly used to test phenylketonuria patients for BH4 responsiveness. This study aimed to analyze differences between the 24- and 48-hour BLT and the necessity of the 400 mumol/l minimum baseline phenylalanine concentration. METHODS: Data on 186 phenylketonuria patients were collected. Patients were supplemented with phenylalanine if phenylalanine was /= 30% reduction in phenylalanine concentration at >/= 1 time point. RESULTS: Eighty-six (46.2%) patients were responsive. Among responders 84% showed a >/= 30% response at T = 48. Fifty-three percent had their maximal decrease at T = 48. Fourteen patients had >/= 30% phenylalanine decrease not before T = 48. A >/= 30% decrease was also seen in patients with phenylalanine concentrations

Contains fulltext : 96794.pdf (Publisher’s version ) (Closed access) OBJECTIVES: To examine the relationship between obesity and depressive symptoms taking into account different measures for obesity (body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR)) and different depressive symptom clusters. DESIGN: Cross-sectional population-based survey. SETTING: Baseline data of the Nijmegen Biomedical Study. PARTICIPANTS: One thousand two hundred eighty-four persons aged 50 to 70. MEASUREMENTS: Obesity (BMI, WC, and WHR) and depressive symptoms were measured, the latter using the Beck Depression Inventory (BDI). Principal components analysis of the BDI items yielded two factors, one representing a cognitive-affective symptom cluster and the other a somatic-affective symptom cluster. Multiple regression analyses corrected for confounders were conducted for each measure of obesity, with separate models testing the BDI sum score and the depression symptom clusters. RESULTS: BMI was significantly associated with BDI sum score (beta=0.12, P

Contains fulltext : 98491.pdf (Publisher’s version ) (Open Access) CONTEXT: Obesity induces low-grade inflammation that may promote the development of insulin resistance. IL-1 is one of the key inflammatory factors. OBJECTIVE: The objective of the study was to demonstrate improvement of insulin sensitivity by blocking IL-1. DESIGN: This was a randomized, double-blind, crossover study. SETTING: The study was based on ambulatory care. PARTICIPANTS: Participants included nondiabetic, obese subjects with the metabolic syndrome. INTERVENTION: Intervention included 150 mg anakinra sc once daily or matching placebo for 4 wk. MAIN OUTCOME MEASURE: Insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. RESULTS: A total of 13 of 19 subjects completed the study. Although anakinra treatment resulted in a significantly lower level of inflammation illustrated by a reduction in circulating C-reactive protein concentrations and leukocyte numbers, insulin sensitivity was not significantly different after anakinra treatment (2.8 x 10(-2) +/- 0.5 x 10(-2)) compared with placebo treatment (2.4 x 10(-2) +/- 0.3 x 10(-2) mumol/kg(-1) . min(-1) . pmol(-1), P = 0.15). Adipose tissue examination, performed to analyze local effects of IL-1 receptor antagonist, showed an increased influx of macrophages after treatment with anakinra most likely due to an injection site reaction caused by the vehicle (0.28 +/- 0.05 vs. 0.11 +/- 0.01 macrophages per adipocyte, P = 0.005). The differences in individual subject insulin sensitivity after anakinra as compared with placebo between subjects were negatively correlated with macrophage infiltration into the adipose tissue (r(2) = 0.46, P = 0.01). The disposition index increased significantly after anakinra treatment (P = 0.04), reflecting an improvement in beta-cell function. CONCLUSIONS: Our results suggest that anakinra does not improve insulin sensitivity in obese, insulin-resistant, nondiabetic subjects.

Item does not contain fulltext The main debate in the treatment of Phenylketonuria (PKU) is whether adult patients need the strict phenylalanine (Phe)-restricted diet. Physicians and patients lack evidence-based guidelines to help them make well-informed choices. We have carried out the first randomised double-blind placebo-controlled trial into the effects of short-term elevation of Phe levels on neuropsychological functions and mood of adults with PKU. Nine continuously treated adults with PKU underwent two 4-week supplementation periods: one with Phe, mimicking normal dietary intake, and one with placebo in randomly allocated order via a randomisation coding list in a double-blind cross-over design. A set of neuropsychological tests (Amsterdam Neuropsychological Tasks) was administered at the end of each study period. In addition, patients and for each patient a friend or relative, completed weekly Profile of Mood States (POMS) questionnaires, evaluating the patients' mood. Phe levels were measured twice weekly. Mean plasma Phe levels were significantly higher during Phe supplementation compared with placebo (p = 0.008). Neuropsychological tests demonstrated an impairment in sustained attention during Phe supplementation (p = 0.029). Both patients and their friend or relative reported lower scores on the POMS questionnaires during Phe supplementation (p = 0.017 and p = 0.040, respectively). High plasma Phe levels have a direct negative effect on both sustained attention and on mood in adult patients with PKU. A Phe-restricted "diet for life" might be an advisable option for many.

Contains fulltext : 87537.pdf (Publisher’s version ) (Open Access) 3-Hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are effective in the primary and secondary prevention of cardiovascular events. Although originally developed to improve lipid profile, statins have demonstrated a surplus of beneficial pleiotropic effects, including improved endothelial function, reduced inflammation, and increased tolerance to ischemia-reperfusion injury. In preclinical studies, increased ecto-5'-nucleotidase activity, the key enzyme in extracellular adenosine formation, plays an important role in these effects. Because human data are absent, we explored the effects of rosuvastatin on ecto-5'-nucleotidase activity and the clinical relevance of increased extracellular adenosine during ischemia in humans in vivo. The forearm vasodilator responses to 3 increasing periods of forearm ischemia (2, 5, and 13 minutes) were determined during placebo and caffeine (an adenosine receptor antagonist) infusion into the brachial artery. At the end of an 8-day treatment period with rosuvastatin (20 mg per day), this whole procedure was repeated. During both experiments, ecto-5'-nucleotidase activity was determined. Vasodilator responses are expressed as the percentage increase in forearm blood flow ratio from baseline. Rosuvastatin increased ecto-5'-nucleotidase activity by 49+/-17% and enhanced the vasodilator response after 2, 5, and 13 minutes of ischemia in the absence (146+/-19, 330+/-26, and 987+/-133 to 312+/-77, 566+/-107, and 1533+/-267) but not in the presence of caffeine (98+/-25, 264+/-54, and 727+/-111 versus 95+/-19, 205+/-34, and 530+/-62). Rosuvastatin increases extracellular formation of adenosine in humans in vivo probably by enhancing ecto-5'-nucleotidase activity. This action results in the improvement of reactive hyperemia and may further enhance the clinical benefit of statins, in particular in conditions of ischemia. 01 oktober 2010

Contains fulltext : 88047.pdf (Publisher’s version ) (Closed access) AIMS: Alpha-adrenergic receptor-mediated vasoconstriction might underlie the insulin resistance seen in conditions associated with increased sympathetic tone, like chronic heart failure (CHF). Alpha-adrenergic receptor blockade by phentolamine could improve forearm blood flow (FBF) and forearm glucose uptake (FGU) in CHF patients. METHODS AND RESULTS: In 8 CHF patients and in 12 healthy volunteers, FBF (plethysmography) and FGU were measured in both forearms during a 150 min hyperinsulinaemic euglycaemic clamp procedure. During the final 30 min of the clamp, phentolamine was infused into one arm (experimental arm) at a dose of 5.0 mug; min(-1) dL(-1) of forearm volume. Insulin infusion (t = 0-120 min) increased FGU in the two groups, without affecting FBF. In the CHF group, alpha-adrenergic receptor blockade by phentolamine (t = 120-150 min) further increased FGU in the experimental arm from 3.0 +/- 0.7 to 5.0 +/- 0.9 mumol min(-1) dL(-1) (P = 0.03). Forearm glucose uptake in the contralateral forearm remained unchanged. In the control group, phentolamine infusion did not increase FGU in the experimental forearm. The increase in blood flow in response to phentolamine was similar in both groups (CHF: 2.1 +/- 0.3-7.5 +/- 1.7 mL min(-1) dL(-1), P < 0.001; controls 1.5 +/- 0.2-5.5 +/- 0.8 mL min(-1) dL(-1), P < 0.001 for both, CHF vs. control, P = 0.2). Phentolamine did not affect FBF in the control arm in either group. CONCLUSION: Alpha-adrenergic receptor blockade improves FGU in CHF patients. As the increase in FBF is similar in controls and CHF patients, this might be explained by an improved glucose-extraction capacity in CHF patients. 01 oktober 2010

Objectives: Total enteral nutrition (TEN) is frequently used as monotherapy in children with Crohn disease to prevent steroid toxicity. Liver disease is a known complication in inflammatory bowel disease, and liver enzymes are regularly obtained in these patients. Patients and Methods: Prospective follow-up of liver enzymes was performed in 11 new consecutive patients ages 7.6 to 17.1 years who were primarily treated with TEN for 6 weeks. Liver enzymes were measured before starting TEN and after 3, 6, and 12 weeks. Results: At the beginning of TEN, the mean aspartate aminotransferase (ASAT) was 18.4U/L and the mean alanine aminotransferase (ALAT) 17.1 U/L. The mean ASAT and ALAT were 202.0 U/L and 269.0 U/L after 3 weeks and 109.6U/L and 180.9U/L at 6 weeks. After 12 weeks values decreased to 22.8 U/L (ASAT) and 20.9 U/L (ALAT). Overall, 9 of 11 patients had transient elevated ASAT and 10 patients showed elevated ALAT. Gamma-glutamyl transpeptidase was slightly elevated in 3 patients during therapy, but alkaline phosphatase and bilirubin showed no changes. None of the patients developed liver disease during follow-up, and prolonged clinical remission was achieved in 9 patients. Conclusions: This study shows that TEN can be associated with transient hypertransaminasemia without evidence of liver disease. We hypothesise that insulin resistance in patients with Crohn disease in combination with standard TEN formulae can result in transient hepatic steatosis causing the hypertransaminasemia. For the clinician it is important to be aware of this benign TEN-associated condition to prevent unnecessary investigations.

Contains fulltext : 88419.pdf (Publisher’s version ) (Closed access) OBJECTIVE: To obtain information about the actual use of health care facilities by undocumented women and to identify obstacles they experience in accessing health care facilities. METHODS: A mixed methods study, with structured questionnaires and semi-structured interviews, was chosen to obtain a complete understanding. One-hundred undocumented women were recruited. Diversity was sought according to age, origin and reason for being undocumented. RESULTS: Undocumented female immigrants have unmet health care needs (56%) and low health care utilisation. Sixty-nine per cent of the women reported obstacles in accessing health care facilities. These included many personal obstacles such as shame, fear and/or lack of information. Poor language proficiency (OR 0.28;. CI 0.09-0.90) reduces utilisation of primary health care services. CONCLUSION: Health care utilisation of undocumented women is low. Undocumented women refrain from seeking health care because of personal obstacles. These women need to be identified and informed about their rights, the health care system and the duty of professional confidentiality of doctors. Finally, institutional obstacles to access care should be removed since they strengthen reluctance to seek help. 01 oktober 2010

Item does not contain fulltext Conventionally, atherogenic dyslipidemias have been defined by elevated levels of triglyceride and/or LDL cholesterol. However, cholesterol and triglycerides are not metabolically and physically independent entities. Rather, they are constituents of the atherogenic apolipoprotein B (apoB) particles, which differ in their origin and their metabolic function. Moreover, the risk of vascular disease is not related to the plasma concentration of cholesterol or triglyceride per se, but to the number, composition and size of the apoB particles, within which the cholesterol and triglycerides are contained. After all, the entire apoB particle--rather than individual cholesterol or triglyceride molecules--enters and is trapped within the arterial wall, and this particle initiates and sustains the process that results in atherosclerosis. Accordingly, we suggest a change of name and focus from dyslipidemias to dyslipoproteinemias. Virtually all the atherogenic apoB dyslipoproteinemias can be specifically identified on the basis of plasma levels of cholesterol, triglyceride and apoB. Not only does this enable an accurate diagnosis in the individual, but the major familial dyslipoproteinemias can be identified as well. Here, we review the diagnostic algorithm for apoB dyslipoproteinemias and provide, for the first time, a treatment plan on the basis of a reduction of atherogenic lipoprotein particles rather than plasma lipids. 01 juni 2010

Contains fulltext : 88642.pdf (Publisher’s version ) (Closed access) BACKGROUND: Heterozygous familial hypercholesterolemia (heFH) is a common autosomal dominant hereditary disorder caused by mutations in the LDL-receptor gene that lead to elevated plasma levels of low-density lipoprotein-cholesterol (LDL-c). Robust lowering of LDL-c levels is essential for risk reduction of premature cardiovascular diseases and early death. European and Dutch guidelines recommend to treat LDL-c to plasma levels or=2.5mmol/l, was acceptance of a higher target LDL-c level by the treating physician. An alternative treatment goal of >50% LDL-c reduction, as recommended in the NICE guidelines, was achieved in 47% of patients with an LDL-c >or=2.5mmol/l and not using maximum therapy. CONCLUSION: Only a small proportion of patients with heFH reaches the LDL-c treatment target of

Contains fulltext : 89087.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients. METHODS: Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations. RESULTS: During discontinuation of statin therapy, MSNA was significantly increased (73 +/- 4 vs. 56 +/- 5 and 52 +/- 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 +/- 3 burst/min without statin vs. 32 +/- 3 and 28 +/- 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 +/- 0.04 without statin vs. 0.29 +/- 0.04 and 0.22 +/- 0.04 during statin, p < 0.05; total normalized MSNA 15.70 +/- 2.78 without statin, vs. 9.28 +/- 1.41 and 6.56 +/- 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected. INTERPRETATION: Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA. 01 april 2010

Contains fulltext : 89272.pdf (Publisher’s version ) (Open Access) BACKGROUND: Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS: We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS: During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P

Contains fulltext : 88255.pdf (Publisher’s version ) (Closed access) BACKGROUND: To compare apolipoprotein B (apoB), non-high-density lipoprotein-cholesterol (non-HDL-c) and low-density lipoprotein-cholesterol (LDL-c) for identifying individuals with a deteriorated cardiovascular (CV) risk profile, including a panel of subclinical atherosclerosis measurements and prevalent cardiovascular disease (CVD) in a Dutch population-based cohort. METHODS: Clinical and biochemical measurements and a panel of noninvasive parameters of subclinical atherosclerosis were determined in 1517 individuals, aged 50-70 years. RESULTS: Both men and women with increasing levels of apoB and non-HDL-c were more obese, had higher blood pressure and fasting glucose levels, and a more atherogenic lipid profile. Furthermore, compared to the reference group (composed of those with apoB, non-HDL-c and LDL-c levels in the bottom quartiles), participants with high apoB and high non-HDL-c levels had a lower ankle-brachial index at rest (-3.5% and -3.1%, respectively) and after exercise (-6.3% and -4.7%, respectively), a thicker near wall (+4.8% and +4.2%, respectively), far wall (both +6.2%), and mean intima-media thickness (+5.7% and +5.3%, respectively) and more plaques (+54.2% and +54.3%, respectively). In addition, they also showed increased stiffness parameters (e.g. pulse wave velocity both +3.6%). Less clear differences in CV risk profile and subclinical atherosclerosis parameters were observed when participants were stratified by LDL-c level. Furthermore, apoB but not LDL-c detected prevalent CVD, and non-HDL-c only detected prevalent CVD in men. The discriminatory power for prevalent CVD expressed as area under the receiver operating characteristic curve was 0.60 (P < 0.001) for apoB, 0.57 (P = 0.001) for non-HDL-c and 0.54 (P = 0.108) for LDL-c. CONCLUSION: Our data support the use of first apoB and secondly non-HDL-c above LDL-c for identifying individuals from the general population with a compromised CV phenotype. 01 december 2010

Contains fulltext : 89861.pdf (Publisher’s version ) (Closed access) Ultrasonography can detect structural muscle changes caused by neuromuscular disease. Quantitative analysis is the preferred method to determine if ultrasound findings are within normal limits, but normative data are incomplete. The purpose of this study was to provide normative muscle ultrasonography data for muscle thickness and echo intensity for five different muscle groups in adults. Bilateral scans of the sternocleidomastoid, biceps brachii/brachialis, forearm flexor group, quadriceps femoris, and tibialis anterior were made in 95 volunteers, aged 17-90 years. Both muscle thickness and echo intensity showed gender differences and a muscle-specific non-linear correlation with age. The muscles of the upper extremities showed right-left differences. These data demonstrate the effect of age on muscle characteristics and provide normative values that can be used in clinical practice. 01 januari 2010

Item does not contain fulltext BACKGROUND: Guidelines have set goals for risk factor management in chronic kidney disease (CKD) patients. These goals are often not met. In this analysis, we set out to assess the quality of risk factor management in CKD and to identify factors that determine the quality of care (QoC). For that purpose, baseline data of the MASTERPLAN (Multifactorial Approach and Superior Treatment Efficacy in Renal Patients with the Aid of Nurse practitioners) study have been used. MASTERPLAN is a multicentre study which evaluates the effect of a multifactorial intervention in prevalent CKD patients on cardiovascular (CV) events and progression of kidney failure. METHODS: QoC was quantified using a score based on the number of 11 defined treatment goals on target. The maximum score per patient was 11. RESULTS: The average (+/-SD) QoC score was 6.7 (+/-1.5). The average score per centre ranged from 5.9 to 6.9. In a multivariable analysis, centre proved to be a significant, independent determinant of QoC with a difference up to 0.7 between centres. This difference remained when adjustments were made for those risk factors primarily treated by pharmacotherapy. Other factors that were significantly related to the QoC were estimated glomerular filtration rate, Caucasian race, diabetes mellitus, diabetic nephropathy as cause of kidney disease and previous kidney transplantation. CONCLUSIONS: In CKD patients, risk factors for progression of kidney failure and CV events were inadequately controlled. Treatment centre proved to be an important determinant of QoC. This data may point towards the physician's interest and preference as important determinants of QoC. This is a potentially modifiable determinant of the quality of patient care [Trial registration ISRCTN registry: 73187232 (http://isrctn.org)]. 01 november 2010

Physical inactivity is a potent stimulus for vascular remodeling, leading to a marked decrease in conduit artery diameter. However, little is known about the impact of physical inactivity on artery wall thickness or wall:lumen ratio or the potential of exercise countermeasures to modify artery wall thickness. The purpose of the study was to examine the impact of 60 days of bed rest, with or without exercise countermeasures, on carotid and superficial femoral artery wall thickness. Eighteen men were assigned to bed rest (second Berlin Bed Rest Study) and randomly allocated to control, resistive exercise, or resistive vibration exercise. Both exercise countermeasures were applied 3 times per week while the subjects were in the supine position on the bed. Sonography was used to examine baseline diameter and wall thickness of the carotid and femoral arteries. Bed rest decreased diameter of the superficial femoral artery ( P =0.001) but not the carotid artery ( P =0.29). Bed rest induced a significant increase in carotid and superficial femoral artery wall thickness ( P =0.007 and 0.03) and wall:lumen ratio ( P =0.009 and 0.001). Exercise prevented the increase in wall thickness of the carotid artery. In addition, exercise partly prevented the increased wall:lumen ratio in the superficial femoral artery. In conclusion, 8 weeks of bed rest resulted in ≈20% increase in conduit artery wall thickness. Exercise countermeasures completely (carotid artery) or partly (superficial femoral artery) abolished the increase in wall thickness. These findings suggest that conduit artery wall thickness, a vascular characteristic associated previously with atherosclerosis, can rapidly adapt to physical inactivity and exercise in humans.

Contains fulltext : 87820.pdf (Publisher’s version ) (Closed access) The aim of these analyses was to examine the efficacy of the intensive gliclazide MR-based glucose lowering regimen used in the ADVANCE trial in lowering the level of glycated haemoglobin (HbA1c). All 11,140 randomised patients were included in analyses of treatment efficacy. Treatment efficacy was also examined in subgroups defined by baseline characteristics and treatments. At the end of 5 years follow-up, the mean HbA1c was reduced from 7.5% at baseline to 6.5% in those on intensive glucose control and to 7.3% in those on standard glucose control. With intensive glucose lowering greater proportions achieved HbA1c levels of < or =7.0%, < or =6.5% and < or =6.0%. With intensive glucose lowering substantial reductions in HbA1c were observed across subgroups defined by baseline age, sex, duration of diabetes, BMI, HbA1c or treatment regimen (p

Contains fulltext : 88447.pdf (Publisher’s version ) (Closed access) AIMS/HYPOTHESIS: The mechanism of fluid-related complications caused by thiazolidinedione derivatives is unclear. One potential mechanism is thiazolidinedione-induced arterial vasodilatation, which results in vascular leakage and a fall in blood pressure, normally counterbalanced by sympathetic activation and subsequent renal fluid retention. We hypothesised that thiazolidinedione-induced vascular leakage will be particularly prominent in patients with autonomic neuropathy. METHODS: We conducted a randomised, double-blind, placebo-controlled, parallel study in 40 patients with type 2 diabetes on insulin treatment recruited from a university medical centre. The randomisation was performed by a central office using a randomisation schedule. Both treatment groups, placebo (n = 21) and rosiglitazone (n = 19), were stratified for sex and level of autonomic neuropathy as assessed by Ewing score (or=2.5). We investigated the effects of 16 weeks of treatment with rosiglitazone 4 mg twice daily on vascular leakage (transcapillary escape rate of albumin, TERalb), body weight, extracellular volume and plasma volume. RESULTS: Thirty-nine patients were included in the analysis. In patients with high Ewing scores (n = 16), rosiglitazone increased TERalb significantly (DeltaTERalb: rosiglitazone +2.43 +/- 0.45%/h, placebo -0.11 +/- 0.15%/h, p = 0.002), while rosiglitazone had no effect in the patients with low Ewing scores (n = 23). Rosiglitazone-induced increases in TERalb and Ewing score at baseline were correlated (r = 0.65, p = 0.02). There was no correlation between Ewing score and rosiglitazone-induced changes in fluid variables. One subject was withdrawn from the study because of atrial fibrillation. CONCLUSIONS/INTERPRETATION: Rosiglitazone may increase vascular leakage in insulin-treated patients with type 2 diabetes with autonomic neuropathy. Autonomic neuropathy did not exaggerate rosiglitazone-induced fluid retention. Therefore, autonomic neuropathy should be considered as a risk factor for thiazolidinedione-induced oedema, not for thiazolidinedione-induced fluid retention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00422955. FUNDING: GlaxoSmithKline. 01 september 2010

Contains fulltext : 88817.pdf (Publisher’s version ) (Closed access) The aim of this study was to assess the feasibility and reproducibility of a simple and nonobtrusive repeated sit-stand maneuver to assess cerebral autoregulation (CA) in healthy old subjects >70 years. In 27 subjects aged 76 (SD 4) years, we continuously measured blood pressure using photoplethysmography and cerebral blood flow velocity in the middle cerebral artery (transcranial Doppler ultrasonography) during 5 min of sitting rest and again during repeated sit-stand maneuvers at 10 s (0.05 Hz) and 5 s (0.1 Hz) intervals. In 11 randomly selected subjects, these measurements were repeated after 3 months. Both maneuvers induced substantial periodic oscillations in pressure and flow. For example, the maneuvers at 0.05 Hz increased the power spectral density (magnitude) of blood pressure and cerebral blood flow velocity oscillations with 16.3 (mm Hg)(2) and 14.5 (cm/s)(2), respectively (p