Gradient over Melody valve in left AV valve position reduces with beta blockade.

The Melody valve, designed for implantation into the pulmonary outflow tract, can also be used to treat the pathology of atrioventricular (AV) valves. Increasing gradients are seen as an indication for re-dilating the valve. Our case demonstrates the heart rate dependency of the gradient across a Melody implanted in the left AV valve position in an infant. Beta blockers were used to lower both heart rate and gradient.

Transient thyrotoxicosis during nivolumab treatment.

Two patients presented with transient thyrotoxicosis within 2-4 weeks after starting treatment with nivolumab. This thyrotoxicosis turned into hypothyroidism within 6-8 weeks. Temporary treatment with a beta blocker may be sufficient.

Risk stratification for healthcare planning in women with gestational diabetes mellitus.

BACKGROUND: To identify relevant factors predicting the need for insulin therapy in women with gestational diabetes mellitus (GDM) and secondly to determine a potential 'low- risk' diet-treated group who are likely to have good pregnancy outcomes. METHODS: A retrospective analysis between 2011-2014. Multivariable backward stepwise logistic regression was used to identify the predictors of the need for insulin therapy. To identify a 'low-risk' diet-treated group, the group was stratified according to pregnancy complications. Diet-treated women with indications for induction in secondary care were excluded. RESULTS: A total of 820 GDM women were included, 360 (44%) women required additional insulin therapy. The factors predicting the need for insulin therapy were: previous GDM, family history of diabetes, a previous infant weighing ≥ 4500 gram, Middle-East/North-African descent, multiparity, pre-gestational BMI ≥ 30 kg/m2, and an increased fasting glucose level ≥ 5.5 mmol/l (OR 6.03;CI 3.56-10.22) and two-hour glucose level ≥ 9.4 mmol/l after a 75-gram oral glucose tolerance test at GDM diagnosis. In total 125 (54%) women treated with diet only had pregnancy complications. Primiparity and higher weight gain during pregnancy were the best predictors for complications (predictive probability 0.586 and 0.603). CONCLUSION: In this GDM population we found various relevant factors predicting the need for insulin therapy. A fasting glucose level ≥ 5.5 mmol/l at GDM diagnosis was by far the strongest predictor. Women with GDM who had good glycaemic control on diet only with a higher parity and less weight gain had a lower risk for pregnancy complications.

BMI may underestimate the socioeconomic gradient in true obesity.

BACKGROUND: Body mass index (BMI) does not make a distinction between fat mass and lean mass. In children, high fat mass appears to be associated with low maternal education, as well as low lean mass because maternal education is associated with physical activity. Therefore, BMI might underestimate true obesity in children of low-educated mothers. OBJECTIVE: To investigate the associations of maternal education with fat mass index (FMI), lean mass index (LMI) and BMI. METHODS: In total, 1965 Dutch children from a prospective cohort, aged 5.7 years (standard deviation 0.5), had available data on body composition based on bioelectrical impedance analysis. RESULTS: Maternal education was not associated with BMI after adjustment for confounders. In contrast, children of low-educated mothers had a higher FMI (ß 0.28 95% confidence interval [CI] 0.07; 0.49) and a lower LMI (ß -0.18 95% CI -0.33; -0.03) compared with children of high-educated mothers. CONCLUSIONS: This suggests that BMI underestimates the educational gradient of childhood obesity.

Occurrence of CCSVI in patients with MS and its relationship with iron metabolism and varicose veins.

BACKGROUND AND PURPOSE: A new treatable venous disorder, chronic cerebrospinal venous insufficiency (CCSVI), has been proposed in patients with multiple sclerosis (MS). Its relationship with iron metabolism is suggested, but has not been examined prospectively. METHODS: We performed extra- and transcranial echo colour Doppler (ECD) in 90 patients with MS and 41 healthy controls (HC). Indices of iron metabolism and the presence of peripheral signs of impaired venous flow were also examined. RESULTS: The ECD examination showed CCSVI in 8 (9%) of the 90 patients with MS and 0 HC (P = 0.11). The 8 CCSVI-positive MS patients were older (P = 0.02), had less often relapsing-remitting-MS (P = 0.02) and had more neurological disability assessed by expanded disability status scale (EDSS, P = 0.001) and longer duration of disease (P = 0.02) in comparison with the 82 CCSVI-negative MS patients. Multivariate analysis revealed that EDSS remained an independent factor associated with CCSVI (odds ratio 1.89, 95%CI 1.17-3.05, P-value = 0.009). CCSVI MS patients more often had bilateral telangiectasia at the legs (P = 0.008), reticular veins (P = 0.006) and venous stasis dermatitis (P = 0.004). No relationship was found between CCSVI and impaired iron metabolism in patients with MS. CONCLUSIONS: CCSVI is uncommon and is a secondary epiphenomenon in MS and related to more neurological disability and the presence of varicose veins at the legs.

Impact of wind turbine sound on annoyance, self-reported sleep disturbance and psychological distress.

PURPOSE OF THE RESEARCH: The present government in the Netherlands intends to realize a substantial growth of wind energy before 2020, both onshore and offshore. Wind turbines, when positioned in the neighborhood of residents may cause visual annoyance and noise annoyance. Studies on other environmental sound sources, such as railway, road traffic, industry and aircraft noise show that (long-term) exposure to sound can have negative effects other than annoyance from noise. This study aims to elucidate the relation between exposure to the sound of wind turbines and annoyance, self-reported sleep disturbance and psychological distress of people that live in their vicinity. Data were gathered by questionnaire that was sent by mail to a representative sample of residents of the Netherlands living in the vicinity of wind turbines PRINCIPAL RESULTS: A dose-response relationship was found between immission levels of wind turbine sound and selfreported noise annoyance. Sound exposure was also related to sleep disturbance and psychological distress among those who reported that they could hear the sound, however not directly but with noise annoyance acting as a mediator. Respondents living in areas with other background sounds were less affected than respondents in quiet areas. MAJOR CONCLUSIONS: People living in the vicinity of wind turbines are at risk of being annoyed by the noise, an adverse effect in itself. Noise annoyance in turn could lead to sleep disturbance and psychological distress. No direct effects of wind turbine noise on sleep disturbance or psychological stress has been demonstrated, which means that residents, who do not hear the sound, or do not feel disturbed, are not adversely affected.

Effects of aquifer thermal energy storage on groundwater quality and the consequences for drinking water production: a case study from The Netherlands.

We used data from an aquifer thermal energy storage (ATES) system located 570 m from a public water supply well field in the south of The Netherlands to investigate the relation between production of renewable energy with an ATES system and the production of drinking water. The data show that the groundwater circulation by the ATES system can impact chemical groundwater quality by introducing shallow groundwater with a different chemical composition at greater depth. However, the observed concentration changes are sufficiently small to keep groundwater suitable for drinking water production. Microbiological results showed that the ATES system introduced faecal bacteria in the groundwater and stimulated the growth of heterotrophic micro-organisms. At the studied site this forms no hygienic risk because of the long distance between the ATES wells and the public supply well field A further degradation of either chemical or microbiological groundwater quality however may necessitate additional water treatment which raises the energy requirements. The additional energy requirements for drinking water treatment may be up the same order of magnitude as the harvested energy by the ATES system.

Incidence of venous thromboembolism in patients with Cushing's syndrome: a multicenter cohort study.

CONTEXT: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). OBJECTIVE: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. DESIGN AND SETTING: We conducted a multicenter cohort study at all university medical centers in The Netherlands. PATIENTS: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. MAIN OUTCOME MEASURES: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. RESULTS: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). CONCLUSIONS: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Deficiencies in fat-soluble vitamins in long-term users of somatostatin analogue.

BACKGROUND: Somatostatin analogues are administered to control hormone hypersecretion in acromegaly and carcinoid patients. Somatostatin analogues can increase fat in the stools, which can lead to loss of fat-soluble vitamins. The effect of long-term somatostatin analogue use on vitamin levels remains unknown. AIM: To investigate the prevalence of fat-soluble vitamin deficiencies in long-term somatostatin analogue users. METHODS: All acromegaly and carcinoid patients using somatostatin analogues for ≥ 18 months visiting the University Medical Center Groningen between December 2008 and April 2009 were eligible. Vitamin levels of fat-soluble vitamins in blood, clinical and vitamin-dependent laboratory parameters were collected. RESULTS: In all, 19 acromegaly and 35 carcinoid patients were included. Twelve patients experienced steatorrhoea; two carcinoid patients experienced night blindness. Forty-two (78%) were deficient for one or more vitamins, and 32% (n = 17) had multiple deficiencies. Deficiencies for vitamin A, D, E, K1 and E in erythrocytes occurred in 6%, 28%, 15%, 63% and 58% of the patients. Prevalence of vitamin D, E and K1 deficiencies was similar in both patient groups. Treatment duration did not influence vitamin levels. The length of intestinal resection and age correlated negatively with vitamin A levels. CONCLUSIONS: Fat-soluble vitamin deficiencies are frequent during long-term somatostatin analogue treatment. Therefore, fat-soluble vitamins should be monitored in these patients.

Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome.

OBJECTIVE: Aberrant adrenal expression of various hormone receptors has been identified in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing cortisol hypersecretion regulated by hormones other than ACTH. We aimed to determine aberrant expression of multiple hormone receptors in vivo and in vitro in adrenal tissue of a patient with AIMAH. DESIGN: The design of the study includes clinical case description, and biochemical and immunohistochemical analysis to demonstrate aberrant expression of multiple hormone receptors in AIMAH. METHODS: The subject of the study is a male diagnosed with Cushing's syndrome because of AIMAH. Directly after laparoscopic removal of the adrenals, adrenal tissue was incubated with and without test substances (ACTH, forskolin, arginine vasopressin (AVP), desmopressin, epinephrine, norepinephrine, purified human chorionic gonadotropin (hCG), metoclopramide and the combinations of AVP with ACTH, epinephrine and metoclopramide). LH/hCG-receptor (hCG-R) immunohistochemistry and RT-PCR analyses were performed to demonstrate aberrant expression of LH/hCG-R and V(1-3)-AVPR. RESULTS: AIMAH was characterized by in vivo cortisol responsiveness to AVP and in vitro cortisol responses to AVP, hCG, epinephrine, and norepinephrine suggesting aberrant adrenal expression of the receptors for AVP (the V(1-3)-AVPRs), catecholamines (the beta-AR), and LH (the LH/hCG-R). Incubation with combinations of AVP and ACTH and of AVP with epinephrine induced a stronger cortisol response compared with incubation with the individual agents. Moreover, we demonstrated adrenal V(1-3)-AVPR and LH/hCG-R expression. CONCLUSIONS: AIMAH tissue may simultaneously express multiple aberrant hormone receptors, and individual ligands may potentiate each other regarding cell proliferation and cortisol production.

[Metabolic encephalopathy can be a potentially life-threatening complication from valproic acid]. / Metabole encefalopathie als potentieel levensbedreigende complicatie van valproïnezuur.

In two female patients of 62 and 81 years old, a metabolic encephalopathy was diagnosed which was ascribed to the use of valproic acid. Both had elevated ammonia levels in arterial blood, without hepatic failure. The first patient eventually became comatose and required artificial ventilation. After discontinuation of the valproic acid and with the aid of supportive measures, both women recovered. In patients with an impaired level of consciousness who are using valproic acid, a metabolic encephalopathy caused by this drug should be considered. Elevated levels of ammonia can be found but are not mandatory. Discontinuation of valproic acid will lead to recovery of consciousness.

[The natural course of non-functioning pituitary adenomas]. / Het natuurlijke beloop van het niet-functionerende hypofyseadenoom.

3 patients presented with non-functioning pituitary adenomas: a 50-year-old woman who had an adenoma that had not increased in size for 3 years; a 68-year-old man with an adenoma that was undiagnosed for 5 years and led to pituitary insufficiency and bitemporal hemianopsia; and a 64-year-old woman, who had refused therapy and follow-up after diagnosis of the adenoma 20 years earlier. She was admitted with a hydrocephalus, pituitary insufficiency, and severe visual loss. The clinical symptoms of pituitary adenomas are caused by the mass effects of the tumour and may vary considerably between patients. Transsphenoidal surgery is indicated in cases of suprasellar extension with compression or impending compressing of the optic chiasm. A 'wait-and-see' approach can be used for patients with smaller tumours and no visual field defects. The natural course of these adenomas is such that lifelong follow-up is necessary. Postoperative radiotherapy can be effective in reducing recurrence rates without negative effects on quality of life.

Acromegaly caused by a growth hormone-releasing hormone secreting carcinoid tumour of the lung: the effect of octreotide treatment.

In acromegaly, the overproduction of growth hormone is usually caused by a pituitary adenoma. We report a 74-year-old woman with acromegaly caused by ectopic overproduction of growth hormone-releasing hormone (GHRH), a rare diagnosis. The GHRH appeared to be produced by a carcinoid tumour of the lung. Treatment with monthly long-acting octreotide resulted in a reduction in the symptoms and normalisation of the insulin-like growth factor-I, which has been maintained for more than two years now. A review of literature concerning causes and treatment of ectopic GHRH-producing tumours is presented.

Life-threatening Pneumocystis jiroveci pneumonia following treatment of severe Cushing's syndrome.

We describe two patients with a severe Cushing's syndrome due to ectopic production of ACTH. Both patients developed a life-threatening Pneumocystis jiroveci pneumonia (PCP) shortly after treatment of the hypercortisolism was started by means of inhibition of production of glucocorticoids and glucocorticoid receptor blockade. We presume that the restored immune response elicited the clinical symptoms of the opportunistic, previously subclinical Pneumocystis jiroveci infection. The immunocompromised state and the delicate glucocorticoid balance in patients with a severe Cushing's syndrome necessitate a specific diagnostic and therapeutic approach.

Geochemistry of trace metals in a fresh water sediment: field results and diagenetic modeling.

Concentrations of Fe, Mn, Cd, Co, Ni, Pb, and Zn were determined in pore water and sediment of a coastal fresh water lake (Haringvliet Lake, The Netherlands). Elevated sediment trace metal concentrations reflect anthropogenic inputs from the Rhine and Meuse Rivers. Pore water and sediment analyses, together with thermodynamic calculations, indicate a shift in trace metal speciation from oxide-bound to sulfide-bound over the upper 20 cm of the sediment. Concentrations of reducible Fe and Mn decline with increasing depth, but do not reach zero values at 20 cm depth. The reducible phases are relatively more important for the binding of Co, Ni, and Zn than for Pb and Cd. Pore waters exhibit supersaturation with respect to Zn, Pb, Co, and Cd monosulfides, while significant fractions of Ni and Co are bound to pyrite. A multi-component, diagenetic model developed for organic matter degradation was expanded to include Zn and Ni dynamics. Pore water transport of trace metals is primarily diffusive, with a lesser contribution of bioirrigation. Reactions affecting trace metal mobility near the sediment-water interface, especially sulfide oxidation and sorption to newly formed oxides, strongly influence the modeled estimates of the diffusive effluxes to the overlying water. Model results imply less efficient sediment retention of Ni than Zn. Sensitivity analyses show that increased bioturbation and sulfate availability, which are expected upon restoration of estuarine conditions in the lake, should increase the sulfide bound fractions of Zn and Ni in the sediments.

Three-dimensional measurement and visualization of morphogenesis applied to cardiac embryology.

Volume growth and proliferation are key processes in heart morphogenesis, yet their regionalization during development of the heart has been described only anecdotally. To study the contribution of cardiomyocyte proliferation to heart development, a quantitative reconstruction method was designed, allowing the local mapping of this morphogenetic process. First, a morphological surface reconstruction is made of the heart, using sections stained specifically for cardiomyocytes. Then, by a comprehensive series of image processing steps, local three-dimensional (3D) information of proliferation is obtained. These local quantitative data are then mapped onto the morphological surface reconstruction, resulting in a reconstruction that not only provides morphological information (qualitative), but also displays local information on proliferation rate (quantitative). The resulting 3D quantitative reconstructions revealed novel observations regarding the morphogenesis of the heart.

[Long-term follow-up is indicated after surgery for a phaeochromocytoma]. / Langdurige controle aangewezen na chirurgische behandeling wegens een feochromocytoom.

Two patients presented with symptoms that suggested a recurrence of phaeochromocytoma, 17 and 14 years after a first manifestation of this disease for which they had undergone successful surgery. The first patient, a 57-year-old man, had typical symptoms of phaeochromocytoma and had recently experienced deterioration of the glycaemic control of his diabetes mellitus type 2. After initial evaluation and treatment with alpha-adrenergic blockade and propranolol, he again underwent surgery. In addition to peritoneal metastases confirmed to be caused by malignant phaeochromocytoma he also had a carcinoma of the caecum. The second patient, a 32-year-old woman, complained of headache and palpitations and had liver-enzyme disorders. Ultrasound examination revealed a tumour in the right upper abdomen and a recurrence of phaeochromocytoma was diagnosed; an intact pregnancy was also found. After a healthy son had been born by caesarian section, she underwent debulking of the large intra-abdominal lymph nodes and of two metastases in the lung. At the last follow-up she was under treatment with radioactive 123I-meta-iodobenzylguanidine (123-MIBG) because of residual metastases. Studies report recurrence ofphaeochromocytoma in 8-20% of cases, and such a recurrence may be either benign or malignant. Factors predictive for recurrence are older age, a malignant primary tumour, tumour weight above 60 g, extra-adrenal origin of the tumour and peroperative tumour spill. Long-term follow-up of patients is indicated, even after successful initial surgery.