Severely increased albuminuria in patients with type 2 diabetes mellitus is associated with increased subclinical atherosclerosis in femoral arteries with Na [18F]F activity as a proxy - The DETERMINE study.

BACKGROUND AND AIMS: Sodium [18F]fluoride (Na [18F]F) positron emission tomography imaging allows detailed visualization of early arterial micro-calcifications. This study aims to investigate atherosclerosis manifested by micro-calcification, macro-calcification, and aortic stiffness in patients with type 2 diabetes mellitus (T2DM) with and without albuminuria and severely decreased kidney function. METHODS: A cohort was stratified in four groups (N = 10 per group), based on KDIGO categories (G1-5 A1-3). G1-2A1 non-diabetic controls (median [IQR] estimated glomerular filtration rate (eGFR) in mL/min/1.73 m2 91 [81-104]), G1-2A1 with T2DM (eGFR 87 [84-93], and albumin-creatinin-ratio (ACR) in mg/mmol 0.35 [0.25-0.75]), G1-2A3 with T2DM (eGFR 85 [60-103], and ACR 74 [62-122], and G4A3 with T2DM (eGFR 19 [13-27] and ACR 131 [59-304]). RESULTS: Na [18F]F femoral artery grading score differed significantly in the groups with the highest Na [18F]F activity in A3 groups with T2DM (G1-2A3 with T2DM 228 [100-446] and G4A3 with T2DM 198 [113-578]) from the lowest groups of the G1-2A1 with T2DM (33 [0-93]) and in G1-2A1 non-diabetic controls (75 [0-200], p = 0.001). Aortic Na [18F]F activity and femoral artery computed tomography (CT)-assessed macro-calcification was increased in G4A3 with T2DM compared with G1-2A1 with T2DM (47.5 [33.8-73.8] vs. 17.5 [8.8-27.5] (p = 0.006) and 291 [170-511] vs. 12.2 [1.41-44.3] mg (p = 0.032), respectively). Carotid-femoral pulse wave velocity (PWV)-assessed aortic stiffness was significantly higher in both A3 groups with T2DM compared with G1-2A1 with T2DM (11.15 and 12.35 vs. 8.86 m/s, respectively (p = 0.009)). CONCLUSIONS: This study indicates that the presence of severely increased albuminuria in patients with T2DM is cross-sectionally associated with subclinical arterial disease in terms of micro-calcification and aortic stiffness. Additional decrease in kidney function was associated with advanced macro-calcifications.

A case of late-onset systemic sclerosis with ruptured silicone breast implants.

BACKGROUND: It is still unresolved whether there is a relationship between silicone breast implants (SBIs) and late-onset systemic sclerosis (SSc). CASE DESCRIPTION: A 83-year-old female was diagnosed with limited cutaneous SSc. During follow-up the presence of ruptured SBIs was confirmed. We provide a literature review concerning SBIs and development of SSc, particularly in relation to age of onset. CONCLUSION: Data about age of onset are incomplete and no details on the rupture of SBIs are reported; however, an association between SSc and SBIs possibly exists.

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.

Mast cell leukaemia presenting with multiple osteoporotic fractures in an elderly woman.

Osteoporotic fractures in elderly women are mainly due to postmenopausal bone loss but can sometimes be caused by a disabling haematological disease. We describe an 84-year-old woman suffering from multiple osteoporotic fractures as a manifestation of mast cell leukaemia. Mast cell leukaemia is a rare form of systemic mastocytosis with a poor prognosis and very few therapeutic options. Osteoporotic fractures have seldom been reported as its initial manifestation.

Autonomic dysfunction in diabetes: a consequence of cardiovascular damage.

In 1976, D.J. Ewing showed a clear survival disadvantage for diabetic patients that had 'diabetic autonomic neuropathy', as assessed by heart rate and blood pressure variations during a battery of bedside tests. However, these variations do not solely depend on autonomic nervous system function, but also and possibly to a more important extent on the integrity of cardiovascular autonomic reflex loops. Increased intima media thickness at the site of the baroreceptors, reduced vascular distensibility, endothelial dysfunction and impaired cardiac function contribute to the cardiovascular autonomic dysfunction. Interestingly, these abnormalities are closely associated with the presence of (micro-) albuminuria that is regarded as a reflection of endothelial dysfunction or vascular damage in diabetes mellitus. Modern techniques to assess cardiovascular autonomic, vascular and cardiac function have improved the ability to detect early abnormalities. Analysis of heart rate variability, baroreflex sensitivity, muscle sympathetic nervous activity, LNMAinfusions and advanced echocardiography have shown that it is the interplay between autonomic control and cardiac and vascular properties that determines cardiovascular autonomic function. Moreover, these modern techniques have improved power to predict survival in diabetic patients in comparison with the classical Ewing's bedside tests. In conclusion, cardiovascular damage may be more important in cardiovascular autonomic dysfunction than neural function.

Intravascular lymphoma as an unusual cause of multifocal cerebral infarctions discovered on FDG-PET/CT.

Intravascular large B-cell lymphoma (IVLBCL) is a rare and aggressive variant of diffuse large B-cell lymphoma with frequent involvement of the central nervous system. Its atypical presentation often delays the diagnosis and due to its aggressive behaviour, the diagnosis is made post-mortem in half of the cases. We report a case of a 67-year-old male patient presenting with speech difficulties and balance disturbances in whom a magnetic resonance imaging (MRI) scan showed multiple lesions of the white matter, denoted as embolic infarctions. He was treated for a suspected endocarditis with antibiotics, but deteriorated neurologically with persistent fever. A consecutive FDG -PET /CT revealed an increased uptake in the adrenals, of which a biopsy showed IVLB CL. The patient was successfully treated with systemic R-CHOP with intrathecal methotrexate and achieved complete remission after six cycles of chemotherapy. The potential role of FDG-PET/CT is illustrated by this case leading to an exceptional diagnosis of IVLBCL.

Phlebotomies as a treatment of serious heart failure due to haemochromatosis: a case report.

Haemochromatosis is a disturbance in the iron metabolism leading to excessive accumulation of iron in various organs such as the liver, pancreas, joints, skin, pituitary, testes and heart, with the last mentioned leading to heart failure. In this report we describe a patient with serious heart failure, attributed to homozygosity for C282Y in the haemochromatosis (HFE) gene, in whom repetitive phlebotomies led to normalisation of left ventricular function. (Neth Heart J 2009;17:438-41.).

[Liver cirrhosis in diabetes mellitus; a complication not always recognized]. / Levercirrose bij diabetes mellitus, een niet altijd onderkende complicatie.

Non-alcoholic fatty liver disease is common among diabetic patients and carries the risk of non-alcoholic steatohepatitis (NASH) and progressive fibrosis and cirrhosis. This is illustrated by three patients with diabetes mellitus, two women aged 76 and 59, and a man aged 58. The first patient was referred to our clinic with ascites that appeared to be due to a previously unrecognized NASH associated with diabetes and which resulted in liver cirrhosis. She was treated with diuretics and subsequently remained stable. The male patient, suffering from overweight, had silently developed liver cirrhosis prompting referral to a transplantation centre. For this procedure he was put on a weight reduction programme. The third patient also had diabetes-associated liver cirrhosis, but was referred for transplantation when liver failure became inevitable. Because of the increasing prevalence of overweight and diabetes, there will be an increase in the number of patients with diabetes associated NASH and liver failure requiring transplantation.

The effect of physical, social and psychological factors on drug compliance in patients with mild hypertension.

BACKGROUND: In patients with hypertension noncompliance with drug treatment is between 15 to 54%, and has been recognised as a relevant contributor to the burden of cardiovascular morbidity. Up to 92% of patients experience unpleasant symptoms with their condition and, particularly in these patients, the symptoms experienced may enhance compliance. OBJECTIVE: To simultaneously assess the effects of physical, social and psychological factors on noncompliance. METHODS: Patients with mild hypertension despite drug treatment, from the departments of cardiology and internal medicine, were requested to answer a self-administered questionnaire addressing the presence of physical symptoms as well as psychosocial factors. The questionnaire was based on previously used test batteries and consisted of two lists of physical complaints and four lists addressing the four domains of planned behaviour regarding medical non-adherence according to Baron and Byrne. These domains mainly assess psychosocial factors. Each list consisted of three or more items and each item was scored on fiveto seven-point scales. Mean scores were used for assessment. The lists were also separately assessed for internal consistency and reliability using Cronbach's alphas. One-way analysis of variance and multivariate analysis of variance (MANOVA) with compliance as outcome variable and the physical, social and psychological variables as indicator variables were used for data analysis. MANOVA was adjusted for multiple testing. RESULTS: Many patients experienced physical symptoms due to hypertension, such as tiredness (31%), hot flushes (28%), headache (24%), reduced daily life energy (23%), palpitations (22%), with 95% confidence intervals between 16 to 38%. Scores for physical symptoms and social factors did not differ between self-reported adherers (n=165) and nonadherers (n=11). However, the score for psychological factors was significantly larger in the adherers than in the non-adherers, 5.05 versus 3.06, p<0.018. The MANOVA showed a significant overall difference between the adherers and non-adherers in the data at p<0.012, which was mainly due to the score for psychological factors. Conclusion. The effect of physical symptoms on non-compliance in mildly hypertensive patients is negligible. So is the effect of social factors. Psychological factors such as lacking a sense of guilt, regret and shame are major determinants of non-compliance. Physicians may play an educational role in improving their patients' compliance by addressing these determinants. We should add that the conclusions should be made with reservations, given the small number of non-adherers in our sample. (Neth Heart J 2008;16:197-200.).

[Struma ovarii during pregnancy]. / Struma ovarii tijdens de zwangerschap.

A 41-year-old pregnant woman, gravida 10, para 7, with gestational diabetes, was diagnosed with subclinical hyperthyroidism. At 16-weeks gestation a left-sided unilateral ovarian cyst was discovered. At 37 weeks of pregnancy an elective caesarean section was carried out, due to the transverse presentation caused by the cyst, followed by an adnexectomy. Histological examination showed a struma ovarii, a rare mature ovarian teratoma mainly consisting of thyroid tissue. There was no evidence of malignancy.

[Diagnostic image (400). A woman with a smooth tongue surface. Pernicious anaemia]. / Diagnose in beeld (400). Een vrouw met een gladde tong. Atrofische glossitis bij pernicieuze anemie.

A 49-year-old woman with exertional dyspnoea had a pale skin and an atrophic tongue due to pernicious anaemia.

[Gout as an unusual cause of pelvic pain]. / Jicht als ongebruikelijke oorzaak van bekkenpijn.

An 89-year-old woman was admitted for high fever and debilitating pelvic pain, notably in the pubic area. Physical examination revealed multiple gouty tophi in her hands and feet. Laboratory investigation revealed severe leukocytosis and a sharply increased C-reactive protein level. The patient was treated with broad-spectrum antibiotics in view of the possibility of a serious bacterial infection, but there was no clinical effect. CT of the pelvis revealed an osteolytic process and a mass anterior to the pubic symphysis. Histological investigation of a biopsy revealed an inflammatory infiltrate with signs of gout. Culture of the biopsy specimen was negative. The diagnosis was confirmed by the finding ofneedle-like urate crystals under the polarizing microscope. After treatment with colchicine and later with prednisone, the symptoms disappeared. She was given uric acid-lowering therapy with allopurinol as a preventive measure.

Increased accumulation of skin advanced glycation end-products precedes and correlates with clinical manifestation of diabetic neuropathy.

AIMS/HYPOTHESIS: The accumulation of AGE is related to the progression of the renal, retinal and vascular complications of diabetes. However, the relationship with diabetic neuropathy remains unclear. We recently showed that skin autofluorescence, measured non-invasively with an AutoFluorescence Reader (AFR), could be used to assess skin AGE accumulation. We evaluated the relationship between skin autofluorescence and the severity of diabetic neuropathy. MATERIALS AND METHODS: Skin autofluorescence in arbitrary units (AU) was assessed in 24 diabetic patients with a history of neuropathic foot ulceration (NP(+)), 23 diabetic patients without clinical neuropathy (NP(-)) and 21 control subjects, using the AFR. Arterial occlusive disease was excluded in all. The severity of foot ulceration was assessed by the Wagner score. Peripheral nerve function was assessed by neurography, measuring motor and sensory nerve conduction velocity and amplitude of the median, peroneal and sural nerves. Heart rate variability (HRV) and baroreflex sensitivity (BRS) were measured by Finapres to assess autonomic nervous function. RESULTS: Autofluorescence was increased in NP(-) compared with control subjects. In NP(+) patients, autofluorescence was further increased and correlated with the Wagner score. Autofluorescence correlated negatively with nerve conduction velocity and amplitude, HRV and BRS in both NP(+) and NP(-) groups. Autofluorescence correlated with age, diabetes duration, mean HbA(1)c of the previous year, serum creatinine level, presence of microalbuminuria and severity of diabetic retinopathy. CONCLUSIONS/INTERPRETATION: Skin autofluorescence correlates with the severity of peripheral and autonomic nerve abnormalities in diabetes, even before being clinically manifest. The AFR may be a convenient and rapid clinical tool for assessing risk of progression of long-term diabetic complications.

Low plasma aldosterone despite normal plasma renin activity in uncomplicated type 1 diabetes mellitus: effects of RAAS stimulation.

BACKGROUND: Data on levels and responsiveness of PRA and aldosterone in type 1 diabetes mellitus are conflicting. Earlier studies were not standardized with respect to the type of diabetes mellitus, the presence of diabetic complications or sodium intake. Therefore, we studied plasma renin activity and plasma aldosterone in uncomplicated type 1 diabetes mellitus by evaluating the effects of endogenous (sodium restriction) and exogenous (angiotensin I infusion) stimulation. DESIGN: Twenty-four type 1 diabetic patients and 24 matched healthy subjects were studied after 1 week of liberal sodium diet (200 mmol 24 h-1) and 1 week of low sodium diet (50 mmol 24 h-1). Angiotensin (Ang)I was infused at 4 and 8 ng kg-1 min-1 during both study days. RESULTS: During liberal and low sodium intake, plasma aldosterone was lower in type 1 diabetic patients compared with healthy subjects both at 08:00 h (P < 0.05) and after a 2-h euglycaemic clamp (P < 0.05), despite similar PRA levels. The correlations between changes in PRA and changes in plasma aldosterone when shifting sodium intake were similar in both groups. During liberal sodium intake, the aldosterone levels after AngI infusion were lower in type 1 diabetic patients, whereas during low sodium they were not different. CONCLUSIONS: Plasma aldosterone was deceased relative to PRA in uncomplicated type 1 diabetic patients, irrespective sodium intake. The responsiveness to sodium restriction was adequate and sodium restriction was able to overcome the decreased plasma aldosterone response to exogenous AngI, which was observed during liberal sodium in diabetic patients. The lower aldosterone is not secondary to diabetic complications and does not depend on the level of sodium intake.

[Diagnostic image (150). A man with renal insufficiency after coronary angiography. Cholesterol embolism after coronary angiography]. / Diagnose in beeld (150). Een man met nierfalen na coronaire angiografie. Cholesterolembolieën na coronaire angiografie.

An 80-year-old man with subacute renal failure had cholesterol emboli in duodenal biopsies and at fundoscopy, most probably caused by coronary angiography after a myocardial infarction two months earlier.

The influence of the ACE ( I/D) polymorphism on systemic and renal vascular responses to angiotensins in normotensive, normoalbuminuric Type 1 diabetes mellitus.

AIM/HYPOTHESIS: The renin-angiotensin-aldosterone system is important in diabetic nephropathy, with the angiotensin-converting-enzyme DD-genotype being a renal risk factor. The D-allele is associated with higher ACE concentrations, but functional consequences in diabetes mellitus are not known. To analyse these consequences, we assessed renal and systemic responsiveness to angiotensin I infusion, with the response to angiotensin II as reference. METHODS: Uncomplicated Type 1 (insulin-dependent) diabetic patients with contrasting genotypes (11 II and 11 DD) were studied, during low (50 mmol/24 h) and liberal (200 mmol/24 h) sodium diet, during a euglycaemic clamp. Angiotensin I was infused at 4 and 8 ng.kg(-1).min(-1), 1 h each, followed by infusions of angiotensin II after a 2-h wash-out period. RESULTS: During low sodium, DD-homozygotes showed higher blood pressure sensitivity to angiotensin I ( DD 21+/-5% vs II 15+/-5%, p<0.01). With liberal sodium, no differences in blood pressure were detected, whereas angiotensin I induced a higher response of ERPF ( DD 40+/-5% vs II 35+/-4%, p<0.05) and RVR ( DD 105+/-20% and II 89+/-16% p<0.05) in DD-homozygotes. Differences were not explained by altered angiotensin II sensitivity. Multiple-linear regression analysis showed that angiotensin I induced responses of blood pressure and renal haemodynamics are higher in subjects carrying the DD-genotype. The magnitude of the responses was modulated by sodium intake and long-term glycaemic control. CONCLUSION/INTERPRETATION: This study showed that responses of blood pressure and renal haemodynamics to angiotensin I are increased in diabetic subjects carrying the DD-genotype. Genotype-associated differences in ACE concentrations could, under certain circumstances, have functional consequences in uncomplicated Type 1 diabetes mellitus.

Sympathetic mediated vasomotion and skin capillary permeability in diabetic patients with peripheral neuropathy.

AIMS/HYPOTHESIS: A loss of sympathetic function could lead to changes in capillary fluid filtration in diabetic patients. We investigated whether a decreased sympathetically mediated vasomotion in the skin in diabetic patients with peripheral neuropathy is associated with an abnormal capillary leakage. METHODS: Three matched groups were studied: 18 diabetic patients with documented peripheral neuropathy (DN), 18 diabetic patients without peripheral neuropathy (D), and 18 healthy control subjects (C). Sensory and motor nerve function of the distal extremities were assessed by standard neurography, and expressed in a sensory-motor nerve function score. Sympathetic vasomotion of the skin microcirculation was assessed by determining the power of blood flow variability in the low-frequency (0.02-0.14 Hz) band by spectral analysis of laser Doppler flowmetry at the median ankle. Skin capillary leakage was evaluated by sodium fluorescein videodensitometry at the same site of the foot. RESULTS: Sympathetically mediated vasomotion of the foot skin microcirculation was lower in diabetic patients with documented peripheral neuropathy compared with diabetic patients without peripheral neuropathy and control subjects (p<0.001). Capillary sodium fluorescein leakage was larger in 18 diabetic patients with documented peripheral neuropathy than in diabetic patients without peripheral neuropathy (p<0.02) and C (p<0.005). Multiple regression analysis disclosed that a reduced sympathetically mediated vasomotion, together with a lower sensory-motor nerve function score, independently contributed to the variance in sodium fluorescein leakage, for 30% (p<0.001) and 17% (p<0.01), respectively. CONCLUSIONS: A loss of sympathetic tone, apart from sensory-motor nerve dysfunction, seems to be a major determinant of an increased capillary permeability in diabetic patients with neuropathy.

[Misleading advertising claims about the indication of doxazosin (Cardura) for type 2 diabetes mellitus and hypertension]. / Misleidende reclame-uitingen over de indicatiestelling van doxazosine (Cardura) bij diabetes mellitus type 2 én hypertensie.

A number of Dutch medical journals have carried an advertisement promoting doxazosin in the treatment of hypertension in patients with type 2 diabetes mellitus. No long-term randomised clinical trials have examined the cardiovascular outcomes of the alpha-adrenergic blockers to which doxazosin belongs. The drug was removed from the largest study into blood pressure and cholesterol reduction ever performed until now (the antihypertensive and lipid-lowering treatment to prevent heart attack trial), due to an increased incidence of cardiovascular events and in particular congestive heart failure. The clinical significance of its insulin-sensitivity improving and lipid-neutralising effects in small-scale, short-term, small patient-group studies are ambiguous. Accordingly, national and international guidelines omitted the drug in their treatment recommendations. The advertisement claims are therefore misleading.