Shared-care survivorship program for testicular cancer patients: safe and feasible.

BACKGROUND: Testicular cancer survivors are at risk for cardiovascular disease, often preceded by early development of cardiovascular risk factors due to chemotherapeutic treatment. Therefore, close collaboration between oncologists and primary care physicians (PCPs) is needed during follow-up to monitor and manage cardiovascular risk factors. We designed a shared-care survivorship program, in which testicular cancer patients visit both their oncologist and their PCP. The objective of this study was to test the safety and feasibility of shared-care follow-up after treatment for metastatic testicular cancer. PATIENTS AND METHODS: The study was designed as an observational cohort study with a stopping rule to check for the safety of follow-up. Safety boundaries were defined for failures in the detection of signals indicating cancer recurrence. Secondary outcomes were the proportion of carried out cardiovascular risk assessments, psychosocial status and patient preferences measured with an evaluation questionnaire. RESULTS: One hundred and sixty-two patients were enrolled (69% of eligible testicular cancer patients). Almost all (99%, n = 150) PCPs of the enrolled patients agreed to participate in the study. In total, 364 primary care visits took place. No failures occurred in the detection of relapsed testicular cancer. Four follow-up visits were considered as failures because of organizational issues, without activation of the stopping rule. Eventually, the safe boundary was crossed indicating that this shared-care model is a safe alternative for follow-up after testicular cancer. Patients were satisfied with the knowledge level of PCPs. PCPs were willing to further extend their role in follow-up care after cancer. CONCLUSIONS: Shared-care follow-up is safe and feasible in this patient population. Patients benefit from personalized care, partly close to their home. Within shared care, PCPs can have an important role in cardiovascular risk management and psychosocial survivorship issues.

Insulin-like factor 3, luteinizing hormone and testosterone in testicular cancer patients: effects of ß-hCG and cancer treatment.

BACKGROUND: Primary hypogonadism (low testosterone and high luteinizing hormone, LH) is present in approximately 20% of testicular cancer (TC) survivors after orchidectomy with or without chemotherapy. OBJECTIVES: We investigated insulin-like factor 3 (INSL3), a novel marker of Leydig cell function, in TC patients. MATERIALS AND METHODS: We analyzed: (I) a cross-sectional cohort of TC patients after orchidectomy with or without chemotherapy (1988-1999) at long-term follow-up (median 36 and 35 years of age at follow-up, respectively) and healthy men of similar age; (II) a longitudinal cohort of chemotherapy-treated TC patients (2000-2008), analyzed before and 1 year after chemotherapy (median 29 years of age at chemotherapy). INSL3, testosterone, and LH were compared between groups and over time and related to pre-chemotherapy ß-hCG levels. RESULTS: In the cross-sectional cohort, TC patients at median 7 years after orchidectomy and chemotherapy (n = 79) had higher LH (p < 0.001), lower testosterone (p = 0.001), but similar INSL3 as controls (n = 40). After orchidectomy only (n = 25), higher LH (p = 0.02), but no differences in testosterone or INSL3 were observed compared to controls. In the longitudinal cohort, patients with normal pre-chemotherapy ß-hCG (≤5 mU/L, n = 35) had increased LH 1 year after chemotherapy compared to pre-chemotherapy (p = 0.001), and no change in testosterone or INSL3. In contrast, patients with high ß-hCG pre-chemotherapy (n = 42) had suppressed LH, markedly elevated testosterone, and low INSL3 at start of chemotherapy, with increased LH, decreased testosterone, and increased INSL3 1 year later (all p < 0.001). DISCUSSION: Changes in LH show that gonadal endocrine function is disturbed before chemotherapy, 1 year later, and at long-term follow-up in chemotherapy-treated TC patients. CONCLUSION: Pre-chemotherapy, ß-hCG-producing tumors affect the gonadal endocrine axis, demonstrated by increased testosterone and decreased LH. INSL3 did not uniformly follow the pattern of testosterone.

Accumulation of advanced glycation end products is associated with macrovascular events and glycaemic control with microvascular complications in Type 2 diabetes mellitus.

AIM: The United Kingdom Prospective Diabetes Study (UKPDS) study showed that glycaemic control (HbA1c ) can predict vascular complications in Type 2 diabetes mellitus. The Diabetes Control and Complications Trial (DCCT) study showed that accumulation of advanced glycation end products (AGEs) from skin biopsies predicts vascular complications in Type 1 diabetes. Previously, we showed that tissue AGEs can be measured non-invasively using skin autofluorescence (SAF). The aim of this study was to compare the predictive value of HbA1c and SAF for new macrovascular events and microvascular complications in people with Type 2 diabetes. METHODS: A prospective cohort study of 563 participants, median age 64 years [interquartile range (IQR) 57-72], diabetes duration of 13 years, from five Dutch hospitals was performed. RESULTS: After a median follow-up of 5.1 (IQR 4.3-5.9) years, 79 (15%) participants had died and 49 (9%) were lost to follow-up. Some 133 (26%) developed a microvascular complication and 189 (37%) a macrovascular event. Tertiles of HbA1c were significantly associated with development of microvascular complications (log rank P = 0.022), but not with macrovascular events. Tertiles of SAF were significantly associated with macrovascular events (log rank P = 0.003). Cox regression analysis showed SAF was associated with macrovascular events: crude hazard ratio (HR) 1.53 (P < 0.001) per unit increase, HR 1.28 (P = 0.03) after correction for UKPDS score. HbA1c was predictive for microvascular complications: crude HR 1.20 (P = 0.004), HR 1.20 (P = 0.004) after correction for UKPDS score. CONCLUSION: This study shows that tissue accumulation of AGEs, assessed by SAF, is associated with development of macrovascular events in people with Type 2 diabetes, whereas HbA1c is associated with the development of microvascular complications.

Diverging effects of diabetes mellitus in patients with peripheral artery disease and abdominal aortic aneurysm and the role of advanced glycation end-products: ARTERY study - protocol for a multicentre cross-sectional study.

INTRODUCTION: Diabetes mellitus is a well-defined risk factor for peripheral artery disease (PAD), but protects against the development and growth of abdominal aortic aneurysm (AAA). Diabetes mellitus is associated with arterial stiffening and peripheral arterial media sclerosis. Advanced glycation end-products (AGEs) are increased in diabetes mellitus and cardiovascular disease. AGEs are known to form cross-links between proteins and are associated with arterial stiffness. Whether AGEs contribute to the protective effects of diabetes mellitus in AAA is unknown. Therefore, the ARTERY (Advanced glycation end-pRoducts in patients with peripheral arTery disEase and abdominal aoRtic aneurYsm) study is designed to evaluate the role of AGEs in the diverging effects of diabetes mellitus on AAA and PAD. METHODS AND ANALYSIS: This cross-sectional multicentre study will compare the amount, type and location of AGEs in the arterial wall in a total of 120 patients with AAA or PAD with and without diabetes mellitus (n=30 per subgroup). Also, local and systemic vascular parameters, including pulse wave velocity, will be measured to evaluate the association between arterial stiffness and AGEs. Finally, AGEs will be measured in serum, urine, and assessed in skin with skin autofluorescence using the AGE Reader. ETHICS AND DISSEMINATION: This study is approved by the Medical Ethics committees of University Medical Center Groningen, Martini Hospital and Medisch Spectrum Twente, the Netherlands. Study results will be disseminated through peer-reviewed journals and scientific events. TRIAL REGISTRATION NUMBER: trialregister.nl NTR 5363.

Cancer treatment induced metabolic syndrome: Improving outcome with lifestyle.

Increasing numbers of long-term cancer survivors face important treatment related adverse effects. Cancer treatment induced metabolic syndrome (CTIMetS) is an especially prevalent and harmful condition. The aetiology of CTIMetS likely differs from metabolic syndrome in the general population, but effective treatment and prevention methods are probably similar. In this review, we summarize the potential mechanisms leading to the development of CTIMetS after various types of cancer treatment. Furthermore, we propose a safe and accessible method to treat or prevent CTIMetS through lifestyle change. In particular, we suggest that a lifestyle intervention and optimization of energy balance can prevent or mitigate the development of CTIMetS, which may contribute to optimal survivorship care.

Vascular fingerprint and vascular damage markers associated with vascular events in testicular cancer patients during and after chemotherapy.

BACKGROUND: Metastatic testicular cancer (TC) can be cured with bleomycin, etoposide and cisplatin (BEP) chemotherapy. This comes at the price of an increased cardiovascular disease risk, not only years afterwards, but also during and shortly after chemotherapy. To prevent cardiovascular events, high-risk patients should be identified. The aim of this study was to assess BEP-chemotherapy induced vascular damage and to find risk factors for early vascular events. PATIENTS AND METHODS: A prospective cohort study was performed in (B)EP treated TC patients. Development of venous and arterial vascular events was assessed. Vascular damage markers (von Willebrand factor [vWF], coagulation factor VIII [FVIII], intima media thickness [IMT]) and cardiovascular risk factors were assessed before and until 1 year after chemotherapy. Before start of chemotherapy a vascular fingerprint was estimated. Presence of ≥3 risk factors was defined as high-risk vascular fingerprint: body mass index >25 kg/m(2), current smoking, blood pressure >140/90 mm Hg, total cholesterol >5.1 and/or low-density lipoprotein >2.5 mmol/L or glucose ≥7 mmol/L. RESULTS: Seventy-three patients were included. Eight (11%) developed vascular events (four arterial events, four pulmonary embolisms). vWF and FVIII increased during chemotherapy, especially in patients with vascular events. Sixteen patients (22%) had a high-risk vascular fingerprint before start of chemotherapy. These patients had arterial events more often (3/16 [19%] versus 1/57 [2%]; p = 0.031) and higher vWF levels and IMT. CONCLUSIONS: Endothelial activation and upregulation of procoagulant activity seem important mechanisms involved in early (B)EP-chemotherapy-induced vascular events. Before chemotherapy, a quarter already had cardiovascular risk factors. A vascular fingerprint could identify patients at risk for arterial events. This vascular fingerprint, when validated, can be used as a tool to select patients who may benefit from preventive strategies.

Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors.

BACKGROUND: The success of cisplatin-based (Platinol, Bristol-Myers Squibb Company, New York, NY, USA) chemotherapy for testicular cancer comes at the price of long-term and late effects related to healthy tissue damage. We assessed and modelled serum platinum (Pt) decay after chemotherapy and determined relationships between long-term circulating Pt levels and known late effects. PATIENTS AND METHODS: In 99 testicular cancer survivors, treated with cisplatin-based chemotherapy, serum and 24-h urine samples were collected during follow-up (1-13 years after treatment). To build a population pharmacokinetic model, measured Pt data were simultaneously analysed, together with cisplatin dose, age, weight and height using the NONMEM software. Based on this model, area under the curve between 1 and 3 years after treatment (Pt AUC1-3 years) was calculated for each patient. Predicted long-term Pt exposure was related to renal function and to late effects of treatment assessed median 9 (3-15) years after chemotherapy. RESULTS: Decay of Pt was best described by a two-compartment model. Mean terminal T1/2 was 3.7 (range 2.5-5.2) years. Pt AUC1-3 years correlated with cumulative cisplatin dose, and creatinine clearance before and 1 year after treatment. Patients with paraesthesia had higher Pt AUC1-3 years (30.9 versus 27.0 µg/l month) compared with those without paraesthesia (P = 0.021). Patients with hypogonadism, elevated LDL-cholesterol levels or hypertension also had higher Pt AUC1-3 years. CONCLUSIONS: Renal function before and after cisplatin treatment is an important determinant of long-term Pt exposure. Known long-term effects of testicular cancer treatment, such as paraesthesia, hypogonadism, hypercholesterolaemia and hypertension, are associated with long-term circulating Pt exposure.

Cancer-drug induced insulin resistance: innocent bystander or unusual suspect.

Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed.

Therapy of endocrine disease: response and toxicity of small-molecule tyrosine kinase inhibitors in patients with thyroid carcinoma: a systematic review and meta-analysis.

CONTEXT: Many tyrosine kinase inhibitors (TKIs) have been studied in patients with thyroid carcinoma (TC). However, the effect and toxicity of various TKIs in differentiated TC (DTC) and medullary TC (MTC) patients have not been directly compared. The aim of the present systematic review and meta-analysis was to systematically summarize response and toxicity of TKIs in TC patients. METHODS: All major databases were systematically searched for publications on TKIs in TC. Primary endpoint was objective response; secondary endpoints were clinical benefit, percentage TKI dose reduction/discontinuation, hand-foot syndrome, diarrhea, and nausea/vomiting. Meta-analysis was performed using an exact likelihood approach and a logistic regression. Pooled percentages and 95% CIs were reported. RESULTS: In total, 22 publications were included. For DTC patients, gefitinib induced no objective responses. Pooled percentage was highest for pazopanib, 49 (95% CI 33-64)%, and was 17 (95% CI 12-24)% for sorafenib. For MTC, gefitinib and imatinib induced no objective responses, whereas sunitinib induced objective response in 43 (95% CI 14-77)%. For vandetanib and cabozantinib, these numbers were 40 (95% CI 34-46)% and 27 (95% CI 22-32)% respectively. Clinical benefit was found in 53 (95% CI 48-59)% of DTC patients on sorafenib, and in 84 (95% CI 79-88)% and 55 (95% CI 49-61)% of MTC patients on vandetanib and cabozantinib respectively. All TKIs were associated with considerable toxicity. CONCLUSION: The currently studied TKIs show a modest response, while side effects are not negligible. Therefore, we suggest to solely consider TKIs in TC patients with rapid progressive disease, for whom the benefits of treatment outweigh toxicity.

Skin autofluorescence and risk of micro- and macrovascular complications in patients with Type 2 diabetes mellitus-a multi-centre study.

AIMS: Skin autofluorescence is a non-invasive marker of advanced glycation end product accumulation. In a previous study, skin autofluorescence correlated with and predicted micro- and macrovascular complications in Type 2 diabetes in a primary care setting. The present cross-sectional study aims to confirm the association between skin autofluorescence and diabetic complications in patients with Type 2 diabetes in a multi-centre secondary care setting. METHODS: We analysed 563 subjects with Type 2 diabetes mellitus from five Dutch hospitals. RESULTS: Median age was 64 years, median duration of diabetes 13 years and median HbA(1c) 58 mmol/mol (7.5%). Sixty-one per cent of patients had microvascular complications (38% nephropathy, 36% retinopathy, 35% neuropathy) and 42% had macrovascular complications. Median UK Prospective Diabetes Study 10-year risk for coronary events was 19%. Median skin autofluorescence was elevated compared with age-matched healthy control subjects: 2.77 (interquartile range 2.39-3.28) vs. 2.46 (2.08-2.84) arbitrary units. Skin autofluorescence was particularly increased in patients with complications: no complications, median 2.56 (2.26-2.90); microvascular complications, 2.79 (2.38-3.29); macrovascular complications, 2.85 (2.41-3.41); both micro- and macrovascular complications, 2.96 (2.56-3.60) arbitrary units, P < 0.001. Logistic regression analysis showed that age, duration of diabetes, renal function, gender, atrial fibrillation and skin autofluorescence were independently associated with macrovascular complications. Multiple regression analysis identified age, smoking, renal function, macrovascular complications and the number of microvascular complications as the determinants of skin autofluorescence. CONCLUSIONS: This study confirms that skin autofluorescence is increased in patients with Type 2 diabetes in a secondary care setting. Skin autofluorescence was associated with macrovascular complications in patients with diabetes and this association was independent of classical risk factors.

Coronary artery calcification score and carotid intima­media thickness in patients with hemophilia.

BACKGROUND/OBJECTIVES: The traditional view that patients with hemophilia are protected against cardiovascular disease is under debate. The aim of the present study was to evaluate the presence and extent of atherosclerosis by coronary artery calcification score (CACS) and carotid intima media thickness (IMT) in patients with hemophilia, and to evaluate their cardiovascular risk profile. METHODS: Sixty-nine patients (51 with hemophilia A; 18 with hemophilia B) were studied [median age: 52 years (interquartile range [IQR] 43­64)]. Cardiovascular risk factors and prior major adverse cardiovascular events (MACEs) were recorded. CACS was derived from electron-beam or dual-source computed tomography, and carotid IMT was assessed by ultrasound measurements and compared with age-specific reference values. RESULTS: The median CACS in all patients was 35 (IQR 0­110) and the geometric mean IMT was 0.80 mm (95% confidence interval [CI] 0.76­0.84); neither was different from the reference values. Patients with a previous MACE (n = 9) had significantly higher CACS and IMT than patients without a previous MACE:CACS median 1013 (IQR 530­1306) vs. 0 (IQR 0­67), and IMT geometric mean 1.09 mm (95% CI 0.95­1.26) vs. 0.76 mm (95% CI 0.73­0.79), both P < 0.001. A higher calculated 10-year cardiovascular risk was related to higher IMT and CACS. CONCLUSION: Patients with hemophilia are not protected against the development of atherosclerosis as measured by CACS and IMT. The extent of atherosclerosis is related to the traditional cardiovascular risk factors. This suggests that traditional cardiovascular risk factors should be monitored and treated in patients with hemophilia.

Medical treatment in carotid artery intervention.

Medical treatment has a pivotal role in the treatment of patients with occlusive carotid artery disease. Large trials have provided the justification for operative treatment besides medical treatment in patients with recent significant carotid artery stenosis two decades ago. Since then, medical therapy has evolved tremendously. Next to aspirin, antiplatelet regimens acting on a different level in the modulation of platelet aggregation have made their entry. Moreover, statin therapy has been introduced. These changes among others in secondary stroke prevention, along with better understanding in life-style adjustments and perioperative medical management, have led to a decrease in stroke recurrence. Secondary prevention is therefore now the most important pillar of medical therapy. It consists of antiplatelet therapy, statins and blood pressure lowering agents in all patients. Small adjustments are recommended for those patients referred for invasive treatment. Moreover, long-term medical treatment is imperative. In this article, we summarize current evidence in literature regarding medical management in patients with previous stroke or TIA.

Longitudinal changes in cardiac function after cisplatin-based chemotherapy for testicular cancer.

BACKGROUND: Cross-sectional studies showed that treatment with cisplatin chemotherapy for testicular cancer is associated with an increased incidence of cardiac dysfunction. We investigated longitudinal progression of and contributing factors to cardiac dysfunction in testicular cancer survivors. PATIENTS AND METHODS: Cardiac assessments were carried out before 10 months (range 7-15 months) and 6.9 years (range 4.9-9.7 years) after start of cisplatin-based chemotherapy, consisting of echocardiography [systolic function (left ventricular ejection fraction, LVEF), diastolic function (myocardial tissue velocities; tissue velocity imaging of early diastole, TVI Et)] and plasma biomarkers (N-Terminal pro brain natriuretic peptide, NT-proBNP; galectin-3). RESULTS: In 37 patients [median age 34 years (range 24-51 years)], the incidence of abnormal TVI Et increased from 0% at baseline and 4.5% at 10 months (in 27 patients) to 16.7% at 6.9 years post-chemotherapy (P = 0.03). One patient developed LVEF <50%; no other systolic abnormalities occurred. Hypertension, obesity and age were associated with larger decreases in TVI Et. Changes in NT-proBNP and galectin-3 were not related to echocardiographic abnormalities. CONCLUSIONS: In this longitudinal cohort study, we observed a gradual decline in diastolic parameters after cisplatin-based chemotherapy for testicular cancer, whereas the rate of systolic dysfunction remains low. The association of larger declines in diastolic parameters with hypertension and obesity stresses the need to monitor and treat cardiovascular risk factors.

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.

Skin autofluorescence and glycemic variability.

BACKGROUND: Accumulation of advanced glycation end products (AGEs) is accelerated during glycemic and oxidative stress and is an important predictor of complications in diabetes mellitus (DM). STUDY DESIGN: Here we both review and present original data on the relationship between skin autofluorescence (SAF), a noninvasive measure of AGEs, and short- and intermediate-term glycemic variations. RESULTS: Acute changes in glucose levels during an oral glucose tolerance test in 56 persons with varying degrees of glucose tolerance did not influence SAF. AGE-rich meals result in a transient postprandial rise in SAF of 10% 2-4 h later. This could not be attributed to meal-induced glycemic changes and is probably caused by the AGE content of the meal. In type 1 DM major intermediate-term improvements of glycemic control as depicted by multiple hemoglobin A1c (HbA1c) measurements were associated with lower skin AGE levels. In a well-controlled, stable type 2 DM cohort, only a weak correlation was found between SAF and HbA1c. In both studies skin AGE/SAF levels predicted complications of diabetes with an accuracy superior to that of HbA1c. SAF has also been proposed as a new tool in diagnosing impaired glucose tolerance (IGT) and DM. It proved to be more sensitive than either fasting glucose or HbA1c. CONCLUSIONS: SAF is not influenced by short-term glycemic variations. AGE-rich meals may, however, cause a transient rise postprandially. There is a weak correlation between SAF or skin AGEs and current or time-integrated HbA1c levels. SAF has strong added value in risk prediction of complications of diabetes and is a promising tool for early detection of diabetes and IGT.

Advanced glycation end products in renal failure: an overview.

The article aims to present an overview of the existing knowledge on advanced glycation end products (AGE). They are moieties that bind to proteins, but also lipids and nuclear acids. AGE are formed during glycation and oxidative stress. Accumulation of AGE occurs especially in diabetes and chronic renal failure and plays a major pathogenetic role. The deleterious effects of AGE result from cross-linking of proteins and activation of the receptor for advanced glycation end products. AGE accumulation can be noninvasively assessed by the skin autofluorescence reader. In diabetics, the skin autofluorescence predicts cardiac mortality and the occurrence of macro- and microvascular complications. In patients on haemodialysis, skin autofluorescence is highly elevated and predicts mortality. After renal transplantation AGE accumulation is lower than during haemodialysis, but still remains elevated and is a strong risk factor for chronic renal transplant dysfunction. Some of the potential methods to intervene with AGE accumulation are discussed in this article.

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.

Increased alpha-linolenic acid intake lowers C-reactive protein, but has no effect on markers of atherosclerosis.

OBJECTIVE: To investigate the effects of increased alpha-linolenic acid (ALA)-intake on intima-media thickness (IMT), oxidized low-density lipoprotein (LDL) antibodies, soluble intercellular adhesion molecule-1 (sICAM-1), C-reactive protein (CRP), and interleukins 6 and 10. DESIGN: Randomized double-blind placebo-controlled trial. SUBJECTS: Moderately hypercholesterolaemic men and women (55 +/- 10 y) with two other cardiovascular risk factors (n = 103). INTERVENTION: Participants were assigned to a margarine enriched with ALA (fatty acid composition 46% LA, 15% ALA) or linoleic acid (LA) (58% LA, 0.3% ALA) for 2 y. RESULTS: Dietary ALA intake was 2.3 en% among ALA users, and 0.4 en% among LA users. The 2-y progression rate of the mean carotid IMT (ALA and LA: +0.05 mm) and femoral IMT (ALA:+0.05 mm; LA:+0.04 mm) was similar, when adjusted for confounding variables. After 1 and 2 y, ALA users had a lower CRP level than LA users (net differences -0.53 and -0.56 mg/l, respectively, P < 0.05). No significant effects were observed in oxidized LDL antibodies, and levels of sICAM-1, interleukins 6 and 10. CONCLUSIONS: A six-fold increased ALA intake lowers CRP, when compared to a control diet high in LA. The present study found no effects on markers for atherosclerosis. SPONSORSHIP: The Dutch 'Praeventiefonds'.